Substituted alkyl amido piperidines

ABSTRACT

This invention is directed to compounds which are selective antagonists for melanin concentrating hormone-1 (MCH1) receptors. The invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier. This invention provides a pharmaceutical composition made by combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier. This invention further provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier. This invention also provides a method of reducing the body mass of a subject which comprises administering to the subject an amount of a compound of the invention effective to reduce the body mass of the subject. This invention further provides a method of treating a subject suffering from depression and/or anxiety which comprises administering to the subject an amount of a compound of the invention effective to treat the subject&#39;s depression and/or anxiety.

BACKGROUND OF THE INVENTION

Melanin-concentrating hormone (MCH) is a cyclic peptide originallyisolated from salmonid (teleost fish) pituitaries (Kawauchi et al.,1983). In fish, the 17 amino acid peptide causes aggregation of melaninwithin the melanophores and inhibits the release of ACTH, acting as afunctional antagonist of α-MSH. Mammalian MCH (19 amino acids) is highlyconserved between rat, mouse, and human, exhibiting 100% amino acididentity, but its physiological roles are less clear. MCH has beenreported to participate in a variety of processes including feeding,water balance, energy metabolism, general arousal/attention state,memory and cognitive functions, and psychiatric disorders (for reviews,see Baker, 1991; Baker, 1994; Nahon, 1994; Knigge et al., 1996). Itsrole in feeding or body weight regulation is supported by a recentNature publication (Qu et al., 1996) demonstrating that MCH isoverexpressed in the hypothalamus of ob/ob mice compared with ob/+ mice,and that fasting further increased MCH mRNA in both obese and normalmice during fasting. MCH also stimulated feeding in normal rats wheninjected into the lateral ventricles (Rossi et al., 1997). MCH also hasbeen reported to functionally antagonize the behavioral effects of α-MSH(Miller et al., 1993; Gonzalez et al, 1996; Sanchez et al., 1997); inaddition, stress has been shown to increase POMC mRNA levels whiledecreasing the MCH precursor preproMCH (ppMCH) mRNA levels (Presse etal., 1992). Thus MCH may serve as an integrative neuropeptide involvedin the reaction to stress, as well as in the regulation of feeding andsexual activity (Baker, 1991; Knigge et al., 1996).

Although the biological effects of MCH are believed to be mediated byspecific receptors, binding sites for MCH have not been well described.A tritiated ligand ([³H]-MCH) was reported to exhibit specific bindingto brain membranes but was unusable for saturation analyses, so neitheraffinity nor B_(max) were determined (Drozdz and Eberle, 1995).Radioiodination of the tyrosine at position thirteen resulted in aligand with dramatically reduced biological activity (see Drozdz andEberle, 1995). In contrast, the radioiodination of the MCH analogue[Phe¹³,Tyr¹⁹]-MCH was successful (Drozdz et al., 1995); the ligandretained biological activity and exhibited specific binding to a varietyof cell lines including mouse melanoma (B16-F1, G4F, and G4F-7), PC12,and COS cells. In G4F-7 cells, the K_(D)=0.118 nM and the B_(max) ˜1100sites/cell. Importantly, the binding was not inhibited by α-MSH but wasweakly inhibited by rat ANF (Ki=116 nM vs. 12 nM for native MCH) (Drozdzet al., 1995). More recently specific MCH binding was reported intransformed keratinocytes (Burgaud et al., 1997) and melanoma cells(Drozdz et al., 1998), where photo-crosslinking studies suggest that thereceptor is a membrane protein with an apparent molecular weight of45-50 kDaltons, compatible with the molecular weight range of the GPCRsuperfamily of receptors. No radioautoradiographic studies of MCHreceptor localization using this ligand have been reported as yet.

The localization and biological activities of MCH peptide suggest thatthe modulation of MCH receptor activity may be useful in a number oftherapeutic applications. The role of MCH in feeding is the bestcharacterized of its potential clinical uses. MCH is expressed in thelateral hypothalamus, a brain area implicated in the regulation ofthirst and hunger (Grillon et al., 1997); recently orexins A and B,which are potent orexigenic agents, have been shown to have very similarlocalization to MCH in the lateral hypothalamus (Sakurai et al., 1998).MCH mRNA levels in this brain region are increased in rats after 24hours of food-deprivation (Hervé and Fellman, 1997); after insulininjection, a significant increase in the abundance and stainingintensity of MCH immunoreactive perikarya and fibres was observedconcurrent with a significant increase in the level of MCH mRNA(Bahjaoui-Bouhaddi et al., 1994). Consistent with the ability of MCH tostimulate feeding in rats (Rossi et al., 1997) is the observation thatMCH mRNA levels are upregulated in the hypothalami of obese ob/ob mice(Qu et al., 1996), and decreased in the hypothalami of rats treated withleptin, whose food intake and body weight gains are also decreased(Sahu, 1998). MCH appears to act as a functional antagonist of themelanocortin system in its effects on food intake and on hormonesecretion within the HPA (hypothalamopituitary/adrenal axis) (Ludwig etal., 1998). Together these data suggest a role for endogenous MCH in theregulation of energy balance and response to stress, and provide arationale for the development of specific compounds acting at MCHreceptors for use in the treatment of obesity and stress-relateddisorders.

In all species studied to date, a major portion of the neurons of theMCH cell group occupies a rather constant location in those areas of thelateral hypothalamus and subthalamus where they lie and may be a part ofsome of the so-called “extrapyramidal” motor circuits. These involvesubstantial striato- and pallidofugal pathways involving the thalamusand cerebral cortex, hypothalamic areas, and reciprocal connections tosubthalamic nucleus, substantia nigra, and mid-brain centers(Bittencourt et al., 1992). In their location, the MCH cell group mayoffer a bridge or mechanism for expressing hypothalamic visceralactivity with appropriate and coordinated motor activity. Clinically itmay be of some value to consider the involvement of this MCH system inmovement disorders, such as Parkinson's disease and Huntingdon's Choreain which extrapyramidal circuits are known to be involved.

Human genetic linkage studies have located authentic hMCH loci onchromosome 12 (12q23-24) and the variant hMCH loci on chromosome 5(5q12-13) (Pedeutour et al., 1994). Locus 12q23-24 coincides with alocus to which autosomal dominant cerebellar ataxia type II (SCA2) hasbeen mapped (Auburger et al., 1992; Twells et al., 1992). This diseasecomprises neurodegenerative disorders, including an olivopontocerebellaratrophy. Furthermore, the gene for Darier's disease, has been mapped tolocus 12q23-24 (Craddock et al., 1993). Darier's disease ischaracterized by abnormalities I keratinocyte adhesion and mentalillnesses in some families. In view of the functional andneuroanatomical patterns of the MCH neural system in the rat and humanbrains, the MCH gene may represent a good candidate for SCA2 or Darier'sdisease. Interestingly, diseases with high social impact have beenmapped to this locus. Indeed, the gene responsible for chronic or acuteforms of spinal muscular atrophies has been assigned to chromosome5q12-13 using genetic linkage analysis (Melki et al., 1990; Westbrook etal., 1992). Furthermore, independent lines of evidence support theassignment of a major schizophrenia locus to chromosome 5q11.2-13.3(Sherrington et al., 1988; Bassett et al., 1988; Gilliam et al., 1989).The above studies suggest that MCH may play a role in neurodegenerativediseases and disorders of emotion.

Additional therapeutic applications for MCH-related compounds aresuggested by the observed effects of MCH in other biological systems.For example, MCH may regulate reproductive functions in male and femalerats. MCH transcripts and MCH peptide were found within germ cells intestes of adult rats, suggesting that MCH may participate in stem cellrenewal and/or differentiation of early spermatocytes (Hervieu et al.,1996). MCH injected directly into the medial preoptic area (MPOA) orventromedial nucleus (VMN) stimulated sexual activity in female rats(Gonzalez et al., 1996). In ovariectomized rats primed with estradiol,MCH stimulated luteinizing hormone (LH) release while anti-MCH antiseruminhibited LH release (Gonzalez et al., 1997). The zona incerta, whichcontains a large population of MCH cell bodies, has previously beenidentified as a regulatory site for the pre-ovulatory LH surge(MacKenzie et al., 1984). MCH has been reported to influence release ofpituitary hormones including ACTH and oxytocin. MCH analogues may alsobe useful in treating epilepsy. In the PTZ seizure model, injection ofMCH prior to seizure induction prevented seizure activity in both ratsand guinea pigs, suggesting that MCH-containing neurons may participatein the neural circuitry underlying PTZ-induced seizure (Knigge andWagner, 1997). MCH has also been observed to affect behavioralcorrelates of cognitive functions. MCH treatment hastened extinction ofthe passive avoidance response in rats (McBride et al., 1994), raisingthe possibility that MCH receptor antagonists may be beneficial formemory storage and/or retention. A possible role for MCH in themodulation or perception of pain is supported by the dense innervationof the periaqueductal grey (PAG) by MCH-positive fibers. Finally, MCHmay participate in the regulation of fluid intake. ICV infusion of MCHin conscious sheep produced diuretic, natriuretic, and kaliureticchanges in response to increased plasma volume (Parkes, 1996). Togetherwith anatomical data reporting the presence of MCH in fluid regulatoryareas of the brain, the results indicate that MCH may be an importantpeptide involved in the central control of fluid homeostasis in mammals.

The identification of a G-protein coupled receptor for MCH has recentlybeen published (Chambers et al., 1999; Saito et al., 1999). These groupsidentified MCH as the endogenous ligand for the human orphan G-proteincoupled receptor SLC-1 (Lakaye et al., 1998). The rat homologue of thisreceptor (now called MCH-1) was reported to be localized in regions ofthe rat brain associated with feeding behavior (e.g. dorsomedial andventromedial hypothalamus). The link between MCH-1 and the effects ofMCH on feeding has been strengthened by recent reports on the phenotypeof MCH-1 knockout mice. Two groups have shown independently (Marsh etal, 2002; Chen et al, 2002) that the targeted disruption of the MCH-1receptor gene (MCH-1 knockout) in mice results in animals that arehyperphagic but are lean and have decreased body mass relative towild-type littermates. The decrease in body mass is attributed to anincrease in metabolism. Each group demonstrated that the MCH-1 knockoutmice are resistant to diet-induced obesity, and generally exhibitweights similar to littermates maintained on regular chow.

Finally, synthetic antagonist molecules for the MCH-1 receptor have nowbeen described in the literature. Bednarek et al. (Bednarek et al. 2002)have reported on the synthesis of high affinity peptide antagonists ofMCH-1. In addition, a small molecule antagonist of MCH-1 has beendescribed by Takekawa et al. (Takekawa et al., 2002). This compound,T-226296, exhibits high affinity for the MCH-1 receptor (˜5-9 nM for ratand human MCH-1), and was shown to inhibit food intake induced by theintracerebroventricular application of MCH. These data validate thestrategy of using an MCH-1 receptor antagonist to treat obesity.

Furthermore, in our own studies, we have tested MCH1 antagonists inseveral animal models that are well known as predictive for the efficacyof compounds in humans, see Borowsky, et al. (2002). These experimentsindicate that MCH1 antagonists are useful to treat obesity, depression,anxiety, as well as urinary disorders.

As used in this invention, the term “antagonist” refers to a compoundwhich binds to, and decreases the activity of, a receptor in thepresence of an agonist. In the case of a G-protein coupled receptor,activation may be measured using any appropriate second messenger systemwhich is coupled to the receptor in a cell or tissue in which thereceptor is expressed. Some specific, but by no means limiting, examplesof well-known second messenger systems are adenylate cyclase,intracellular calcium mobilization, ion channel activation, guanylatecyclase and inositol phospholipid hydrolysis. Conversely, the term“agonist” refers to a compound which binds to, and increases activityof, a receptor as compared with the activity of the receptor in theabsence of any agonist.

In one embodiment of this invention, the synthesis of novel compoundswhich bind selectively to the cloned human melanin-concentratinghormone-1 (MCH1) receptor, compared to other cloned G-protein coupledreceptors, and inhibit the activation of the cloned receptors asmeasured in in vitro assays is disclosed. The in vitro receptor bindingassays described hereinafter were performed using various cultured celllines, each transfected with and expressing only a single clonedreceptor.

Furthermore, the compounds of the present invention may also be used totreat abnormal conditions such as feeding disorders (obesity, bulimiaand bulimia nervosa), sexual/reproductive disorders, depression,anxiety, depression and anxiety, epileptic seizure, hypertension,cerebral hemorrhage, congestive heart failure, sleep disturbances, orany condition in which antagonism of an MCH1 receptor may be beneficial.In addition, the compounds of the present invention may be used toreduce the body mass of a subject. Furthermore, the compounds of thepresent invention may be used to treat urinary disorders.

SUMMARY OF THE INVENTION

The present invention provides a compound having the structure:

wherein each R₁ is independently hydrogen; —F; —Cl; —Br; —I; —CN; —NO₂;straight chained or branched C₁-C₇ alkyl, monofluoroalkyl orpolyfluoroalkyl; straight chained or branched C₂-C₇ alkenyl; C₃-C₇cycloalkyl or C₅-C₇ cycloalkenyl; aryl; heteroaryl; —N(R₅)₂;(CH₂)_(m)OR₅; —COR₅; —CO₂R₅; —OCOR₅; —CON(R₅)₂; —N(R₅)COR₅;—N(R₅)CON(R₅)₂; —OCON(R₅)₂ or —N(R₅)CO₂R₅;wherein R₂ is hydrogen; —F; —Cl; —Br; —I; —CN; —(CH₂)_(m)OR₅;—(CH₂)_(m)SR₅; —NH₂; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, polyfluoroalkyl; aryl or heteroaryl, wherein the arylor heteroaryl may be substituted with one or more R₁wherein R₃ is hydrogen, —F; —Cl; —Br; —I; —CN; —(CH₂)_(m)OR₅;—(CH₂)_(m)SR₅; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, polyfluoroalkyl; aryl or heteroaryl, wherein the arylor heteroaryl may be substituted with one or more R₁; or wherein R₂ andR₃ together can be —(CH₂)_(p)—;wherein R₄ is straight chained or branched C₁-C₇ alkyl, monofluoroalkylor polyfluoroalkyl, C₃-C₆ cycloalkyl, C₁-C₇ alkyl-C₃-C₆ cycloalkyl;—N(R₅)₂ or —(CH₂)_(m)OR₅;wherein each R₅ is independently hydrogen; aryl; heteroaryl or straightchained or branched C₁-C₇ alkyl, wherein the alkyl may be substitutedwith an aryl or heteroaryl;wherein each R₆ is independently hydrogen; straight chained or branchedC₁-C₇ alkyl;wherein each R₇ is independently hydrogen; phenyl or straight chained orbranched C₁-C₇ alkyl, wherein the alkyl may be substituted with aphenyl;wherein each m is independently an integer from 0 to 5 inclusive;wherein n is an integer from 1 to 5 inclusive;wherein p is an integer from 2 to 7 inclusive;wherein q is an integer from 0 to 2 inclusive; andwherein each X is independently CR₁ or N, provided that if one X is Nthen the remaining X are CR₁; or a pharmaceutically acceptable saltthereof.

In one embodiment of the invention, the compound is selected from one ofthe specific compounds disclosed in the Detailed Description of theInvention.

In an embodiment of the present invention the compound isenantiomercially pure. In another embodiment of the invention, thecompound is diastereomerically pure. In a further embodiment, thecompound is enantiomercially and diastereomerically pure.

The present invention further provides a pharmaceutical composition thatcomprises a therapeutically effective amount of a compound of thepresent invention and a pharmaceutically acceptable carrier.

The present invention further provides a pharmaceutical composition madeby admixing a compound of the present invention and a pharmaceuticallyacceptable carrier.

The present invention also provides a process for making apharmaceutical composition comprising admixing a compound of the presentinvention and a pharmaceutically acceptable carrier.

The invention further provides a method of treating a subject sufferingfrom an affective disorder selected from the group consisting ofdepression, major depression, bipolar disorder, agoraphobia, specificphobia, social phobia, obsessive-compulsive disorder, post-traumaticstress disorder, acute stress disorder and anxiety comprisingadministering to the subject a therapeutically effective amount of thecompound of the invention. In a separate embodiment of the invention,the disorder is depression or anxiety.

Additionally, the invention further provides a method of treating asubject suffering from a urinary disorder selected from the groupconsisting of urinary incontinence, urge incontinence, urinaryfrequency, urinary urgency, nocturia or enuresis comprisingadministering to the subject a therapeutically effective amount of thecompound of the invention. In a separate embodiment of the invention,the disorder is urinary incontinence.

The invention further provides a method of treating a subject sufferingfrom an eating disorder selected from the group consisting of obesity,bulimia, bulimia nervosa or anorexia nervosa comprising administering tothe subject a therapeutically effective amount of the compound of theinvention. In a separate embodiment of the invention, the disorder isobesity.

DETAILED DESCRIPTION OF THE INVENTION

As used in the present invention, the term “heteroaryl” is used toinclude five and six membered unsaturated rings that may contain one ormore oxygen, sulfur, or nitrogen atoms. Examples of heteroaryl groupsinclude, but are not limited to, carbazole, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, and triazinyl. In addition, the term “heteroaryl” is used toinclude fused bicyclic ring systems that may contain one or moreheteroatoms such as oxygen, sulfur and nitrogen. Examples of suchheteroaryl groups include, but are not limited to, indolizinyl, indolyl,isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl,benzimidazolyl, purinyl, benzoxazolyl, benzisoxazolyl,benzo[b]thiazolyl, imidazo[2,1-b]thiazolyl, cinnolinyl, quinazolinyl,quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,phthalimidyl and 2,1,3-benzothiazolyl. The term “heteroaryl” alsoincludes those chemical moieties recited above which may be substitutedwith one or more of the following: —F, —Cl, —Br, —I, CN, —NO₂, straightchained or branched C₁-C₇ alkyl, straight chained or branched C₁-C₇monofluoroalkyl, straight chained or branched C₁-C₇ polyfluoroalkyl,straight chained or branched C₂-C₇ alkenyl, straight chained or branchedC₂-C₇ alkynyl; C₃-C₇ cycloalkyl, C₃-C₇ monofluorocycloalkyl, C₃-C₇polyfluorocycloalkyl, C₅-C₇ cycloalkenyl. The term “heteroaryl” furtherincludes the N-oxides of those chemical moieties recited above whichinclude at least one nitrogen atom.

In the present invention, the term “aryl” is phenyl or naphthyl.

In the present invention, the term straight chained or branched C₁-C₇alkyl refers to a saturated hydrocarbon having from one to seven carbonatoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl,2-butyl, 2-methly-2-propyl and 2-methly-1-propyl. Similarily, alkenyland alkynyl, respectively, designate such groups having from two toseven carbon atoms, including one double bond and triple bondrespectively, such as ethenyl, propenyl, butenyl, ethynyl, propynyl, andbutynyl. The term, C₃-C₇ cycloalkyl designates a monocyclic carbocyclehaving three to seven carbon atoms, such as cyclopropyl, cyclopentyl,cyclohexyl, etc. The term, C₁-C₇ alkyl-C₃-C₆ cycloalkyl designates asaturated alkyl hydrocarbon substituted with a monocyclic carbocyclering having three to seven carbon atoms attached via the C₁-C₇ alkylmoiety, such as methyl-cyclopropyl, ethyl-cyclopentyl,n-propyl-cyclohexyl, etc.

The invention provides for each pure stereoisomer of any of thecompounds described herein. Such stereoisomers may include enantiomers,diastereomers, or E or Z alkene or imine isomers. The invention alsoprovides for stereoisomeric mixtures, including racemic mixtures,diastereomeric mixtures, or E/Z isomeric mixtures. Stereoisomers can besynthesized in pure form (Nógrádi, M.; Stereoselective Synthesis, (1987)VCH Editor Ebel, H. and Asymmetric Synthesis, Volumes 3 B 5, (1983)Academic Press, Editor Morrison, J.) or they can be resolved by avariety of methods such as crystallization and chromatographictechniques (Jaques, J.; Collet, A.; Wilen, S.; Enantiomer, Racemates,and Resolutions, 1981, John Wiley and Sons and Asymmetric Synthesis,Vol. 2, 1983, Academic Press, Editor Morrison, J). In addition thecompounds of the present invention may be present as enantiomers,diasteriomers, isomers or two or more of the compounds may be present toform a racemic or diastereomeric mixture.

The compounds of the present invention are preferably 80% pure, morepreferably 90% pure, and most preferably 95% pure. Included in thisinvention are pharmaceutically acceptable salts and complexes of all ofthe compounds described herein. The acids and bases from which thesesalts are prepared include but are not limited to the acids and baseslisted herein. The acids include, but are not limited to, the followinginorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid and boric acid. The acids include, but are not limited to,the following organic acids: acetic acid, malonic acid, succinic acid,fumaric acid, tartaric acid, maleic acid, citric acid, methanesulfonicacid, benzoic acid, glycolic acid, lactic acid and mandelic acid. Thebases include, but are not limited to ammonia, methylamine, ethylamine,propylamine, dimethylamine, diethylamine, trimethylamine, triethylamine,ethylenediamine, hydroxyethylamine, morpholine, piperazine andguanidine. This invention further provides for the hydrates andpolymorphs of all of the compounds described herein.

The present invention includes within its scope prodrugs of thecompounds of the invention. In general, such prodrugs will be functionalderivatives of the compounds of the invention which are readilyconvertible in vivo into the required compound. Thus, in the presentinvention, the term “administering” shall encompass the treatment of thevarious conditions described with the compound specifically disclosed orwith a compound which may not be specifically disclosed, but whichconverts to the specified compound in vivo after administration to thepatient. Conventional procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in Design ofProdrugs, ed. H. Bundgaard, Elsevier, 1985. The present inventionfurther includes metabolites of the compounds of the present invention.Metabolites include active species produced upon introduction ofcompounds of this invention into the biological milieu.

This invention further provides a pharmaceutical composition comprisinga therapeutically effective amount of the compound of the invention anda pharmaceutically acceptable carrier. In one embodiment, the amount ofthe compound is from about 0.01 mg to about 800 mg. In anotherembodiment, the amount of the compound is from about 0.01 mg to about500 mg. In yet another embodiment, the amount of the compound is fromabout 0.1 mg to about 250 mg. In another embodiment, the amount of thecompound is from about 0.1 mg to about 60 mg. In yet another embodiment,the amount of the compound is from about 1 mg to about 20 mg. In afurther embodiment, the carrier is a liquid and the composition is asolution. In another embodiment, the carrier is a solid and thecomposition is a tablet. In another embodiment, the carrier is a gel andthe composition is a capsule, suppository or a cream. In a furtherembodiment the compound may be formulated as a part of apharmaceutically acceptable transdermal patch. In yet a furtherembodiment, the compound may be delivered to the subject by means of aspray or inhalant. This invention also provides a pharmaceuticalcomposition made by combining a therapeutically effective amount of thecompound of this invention and a pharmaceutically acceptable carrier.This invention provides a process for making a pharmaceuticalcomposition comprising combining a therapeutically effective amount ofthe compound of this invention and a pharmaceutically acceptablecarrier.

A solid carrier can include one or more substances which may also act asendogenous carriers (e.g. nutrient or micronutrient carriers), flavoringagents, lubricants, solubilizers, suspending agents, fillers, glidants,compression aids, binders or tablet-disintegrating agents; it can alsobe an encapsulating material. In powders, the carrier is a finelydivided solid which is in admixture with the finely divided activeingredient. In tablets, the active ingredient is mixed with a carrierhaving the necessary compression properties in suitable proportions andcompacted in the shape and size desired. The powders and tabletspreferably contain up to 99% of the active ingredient. Suitable solidcarriers include, for example, calcium phosphate, magnesium stearate,talc, sugars, lactose, dextrin, starch, gelatin, cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers are used in preparing solutions, suspensions, emulsions,syrups, elixirs and pressurized compositions. The active ingredient canbe dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fats. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, coloring agents, viscosityregulators, stabilizers or osmoregulators. Suitable examples of liquidcarriers for oral and parenteral administration include water (partiallycontaining additives as above, e.g. cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g. glycols) and their derivatives,and oils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration, the carrier can also be an oily ester such as ethyloleate or isopropyl myristate. Sterile liquid carriers are useful insterile liquid form compositions for parenteral administration. Theliquid carrier for pressurized compositions can be a halogenatedhydrocarbon or other pharmaceutically acceptable propellent.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by for example, intramuscular, intrathecal,epidural, intraperitoneal or subcutaneous injection. Sterile solutionscan also be administered intravenously. The compounds may be prepared asa sterile solid composition which may be dissolved or suspended at thetime of administration using sterile water, saline, or other appropriatesterile injectable medium. Carriers are intended to include necessaryand inert binders, suspending agents, lubricants, flavorants,sweeteners, preservatives, dyes, and coatings. The compound can beadministered orally in the form of a sterile solution or suspensioncontaining other solutes or suspending agents (for example, enoughsaline or glucose to make the solution isotonic), bile salts, acacia,gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitoland its anhydrides copolymerized with ethylene oxide) and the like.

The compound can also be administered orally either in liquid or solidcomposition form. Compositions suitable for oral administration includesolid forms, such as pills, capsules, granules, tablets, and powders,and liquid forms, such as solutions, syrups, elixirs, and suspensions.Forms useful for parenteral administration include sterile solutions,emulsions, and suspensions. Optimal dosages to be administered may bedetermined by those skilled in the art, and will vary with theparticular compound in use, the strength of the preparation, the mode ofadministration, and the advancement of the disease condition. Additionalfactors depending on the particular subject being treated will result ina need to adjust dosages, including subject age, weight, gender, diet,and time of administration. In the subject application a“therapeutically effective amount” is any amount of a compound which,when administered to a subject suffering from a disease against whichthe compounds are effective, causes reduction, remission, or regressionof the disease. In a subject application, a “subject” is a vertebrate, amammal or a human.

This invention provides a method of treating a subject suffering from anabnormality wherein the abnormality is alleviated by decreasing theactivity of an MCH1 receptor which comprises administering to thesubject an amount of a compound of the invention which is an MCH1receptor antagonist effective to treat the subject's abnormality. Inseparate embodiments, the abnormality is a regulation of a steroid orpituitary hormone disorder, an epinephrine release disorder, agastrointestinal disorder, a cardiovascular disorder, an electrolytebalance disorder, hypertension, diabetes, a respiratory disorder,asthma, a reproductive function disorder, an immune disorder, anendocrine disorder, a musculoskeletal disorder, a neuroendocrinedisorder, a cognitive disorder, a memory disorder such as Alzheimer'sdisease, a sensory modulation and transmission disorder, a motorcoordination disorder, a sensory integration disorder, a motorintegration disorder, a dopaminergic function disorder such asParkinson's disease, a sensory transmission disorder, an olfactiondisorder, a sympathetic innervation disorder, an affective disorder suchas depression and anxiety, a stress-related disorder, a fluid-balancedisorder, a seizure disorder, pain, psychotic behavior such asschizophrenia, morphine tolerance, opiate addiction, migraine or aurinary disorder such as urinary incontinence.

The following description of depressive and anxiety disorders is for thepurpose of illustrating the utility of the compounds of this invention.The definitions of depressive and anxiety disorders given below arethose listed in Diagnostic and Statistical Manual of Mental Disorders.4th ed. (DSM-IV; American Psychiatric Association, 1994a) or Diagnosticand Statistical Manual of Mental Disorders. 3rd ed. Revised (DSM-III-R;American Psychiatric Association, 1987). Additional informationregarding these disorders can be found in this reference, as well as theothers cited below, all of which are incorporated herein by reference.Depressive disorders include major depressive disorder and dysthymicdisorder (American Psychiatric Association, 1994a; American PsychiatricAssociation, 1994b). Major depressive disorder is characterized by theoccurrence of one or more major depressive episodes without manic orhypomanic episodes. A major depressive episode is defined as a prominentand relatively persistent depressed or dysphoric mood that usuallyinterferes with daily functioning (nearly every day for at least 2weeks); it should include at least 4 of the following 8 symptoms: changein appetite, change in sleep, psychomotor agitation or retardation, lossof interest in usual activities or decrease in sexual drive, increasedfatigue, feelings of guilt or worthlessness, slowed thinking or impairedconcentration, and a suicide attempt or suicidal ideation (MedicalEconomics Company, 2002); Dysthymic disorder involves a type ofdepression that is not severe enough to be called a major depressiveepisode, but that lasts much longer than major depressive disorder,without high phases.

It is contemplated that the compounds of this invention will beeffective in treating depression in patients who have been diagnosedwith depression by administration of any of the following tests:Hamilton Depression Rating Scale (HDRS), Hamilton depressed mood item,Clinical Global Impressions (CGI)-Severity of Illness. It is furthercontemplated that the compounds of the invention will be effective ininducing improvements in certain of the factors measured in these tests,such as the HDRS subfactor scores, including the depressed mood item,sleep disturbance factor and anxiety factor, and the CGI-Severity ofIllness rating. It is also contemplated that the compounds of thisinvention will be effective in preventing relapse of major depressiveepisodes. Anxiety disorders include panic disorder, agoraphobia with orwithout history of panic disorder, specific phobia, social phobia,obsessive-compulsive disorder, post-traumatic stress disorder, acutestress disorder and generalized anxiety disorder. It is contemplatedthat the compounds of this invention will be effective in treating anyof all of these disorders in patients who have been diagnosed with thesedisorders. Obsessive compulsive disorder is characterized by recurrentand persistent ideas, thoughts, impulses or images (obsessions) that areego-dystonic and/or repetitive, purposeful and intentional behaviors(compulsions) that are recognized by the person as excessive orunreasonable (American Psychiatric Association, 1994a). The obsessionsor compulsions cause marked distress, are time-consuming, orsignificantly interfere with social or occupational functioning. It iscontemplated that the compounds of this invention will be effective intreating obsessions and compulsions in patients who have been diagnosedwith obsessive compulsive disorder by administration of appropriatetests, which may include, but are not limited to any of the following:Yale Brown Obsessive Compulsive Scale (YBOCS) (Goodman, 1989) (foradults), National Institute of Mental Health Global OCD Scale (NIMHGOCS), CGI-Severity of Illness scale. It is further contemplated thatthe compounds of the invention will be effective in inducingimprovements in certain of the factors measured in these tests, such asa reduction of several points in the YBOCS total score. It is alsocontemplated that the compounds of this invention will be effective inpreventing relapse of obsessive compulsive disorder.

Panic disorder is characterized by recurrent unexpected panic attacksand associated concern about having additional attacks, worry about theimplications or consequences of the attacks, and/or a significant changein behavior related to the attacks (American Psychiatric Association,1994a). A panic attack is defined as a discrete period of intense fearor discomfort in which four (or more) of the following symptoms developabruptly and reach a peak within 10 minutes: (1) palpitations, poundingheart, or accelerated heart rate; (2) sweating; (3) trembling orshaking; (4) sensations of shortness of breath or smothering; (5)feeling of choking; (6) chest pain or discomfort; (7) nausea orabdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint;(9) derealization (feelings of unreality) or depersonalization (beingdetached from oneself); fear of losing control; (11) fear of dying; (12)paresthesias (numbness or tingling sensations); (13) chills or hotflushes. Panic disorder may or may not be associated with agoraphobia,or an irrational and often disabling fear of being out in public. It iscontemplated that the compounds of this invention will be effective intreating panic disorder in patients who have been diagnosed with panicdisorder on the basis of frequency of occurrence of panic attacks, or bymeans of the CGI-Severity of Illness scale. It is further contemplatedthat the compounds of the invention will be effective in inducingimprovements in certain of the factors measured in these evaluations,such as a reduction in frequency or elimination of panic attacks, animprovement in the CGI-Severity of Illness scale or a CGI-GlobalImprovement score of 1 (very much improved), 2 (much improved) or 3(minimally improved). It is also contemplated that the compounds of thisinvention will be effective in preventing relapse of panic disorder.

Social anxiety disorder, also known as social phobia, is characterizedby a marked and persistent fear of one or more social or performancesituations in which the person is exposed to unfamiliar people or topossible scrutiny by others (American Psychiatric Association, 1994a).Exposure to the feared situation almost invariably provokes anxiety,which may approach the intensity of a panic attack. The fearedsituations are avoided or endured with intense anxiety or distress. Theavoidance, anxious anticipation, or distress in the feared situation(s)interferes significantly with the person's normal routine, occupationalor academic functioning, or social activities or relationships, or thereis marked distress about having the phobias. Lesser degrees ofperformance anxiety or shyness generally do not requirepsychopharmacological treatment. It is contemplated that the compoundsof this invention will be effective in treating social anxiety disorderin patients who have been diagnosed with social anxiety disorder byadministration of any of the following tests: the Liebowitz SocialAnxiety Scale (LSAS), the CGI-Severity of Illness scale, the HamiltonRating Scale for Anxiety (HAM-A), the Hamilton Rating Scale forDepression (HAM-D), the axis V Social and Occupational FunctioningAssessment Scale of DSM-IV, the axis II (ICD-10) World HealthOrganization Disability Assessment, Schedule 2 (DAS-2), the SheehanDisability Scales, the Schneier Disability Profile, the World HealthOrganization Quality of Life-100 (WHOQOL-100), or other tests asdescribed in Bobes, 1998, which is incorporated herein by reference. Itis further contemplated that the compounds of the invention will beeffective in inducing improvements as measured by these tests, such asthe a change from baseline in the Liebowitz Social Anxiety Scale (LSAS),or a CGI-Global Improvement score of 1 (very much improved), 2 (muchimproved) or 3 (minimally improved). It is also contemplated that thecompounds of this invention will be effective in preventing relapse ofsocial anxiety disorder.

Generalized anxiety disorder is characterized by excessive anxiety andworry (apprehensive expectation) that is persistent for at least 6months and which the person finds difficult to control (AmericanPsychiatric Association, 1994a). It must be associated with at least 3of the following 6 symptoms: restlessness or feeling keyed up or onedge, being easily fatigued, difficulty concentrating or mind goingblank, irritability, muscle tension, sleep disturbance. The diagnosticcriteria for this disorder are described in further detail in DSM-IV,which is incorporated herein by reference (American PsychiatricAssociation, 1994a). It is contemplated that the compounds of thisinvention will be effective in treating generalized anxiety disorder inpatients who have been diagnosed with this disorder according to thediagnostic criteria described in DSM-IV. It is further contemplated thatthe compounds of the invention will be effective in reducing symptoms ofthis disorder, such as the following, excessive worry and anxiety,difficulty controlling worry, restlessness or feeling keyed up or onedge, being easily fatigued, difficulty concentrating or mind goingblank, irritability, muscle tension, or sleep disturbance. It is alsocontemplated that the compounds of this invention will be effective inpreventing relapse of general anxiety disorder.

Post-traumatic stress disorder (PTSD), as defined by DSM-III-R/IV(American Psychiatric Association, 1987, American PsychiatricAssociation, 1994a), requires exposure to a traumatic event thatinvolved actual or threatened death or serious injury, or threat to thephysical integrity of self or others, and a response which involvesintense fear, helplessness, or horror. Symptoms that occur as a resultof exposure to the traumatic event include re-experiencing of the eventin the form of intrusive thoughts, flashbacks or dreams, and intensepsychological distress and physiological reactivity on exposure to cuesto the event; avoidance of situations reminiscent of the traumaticevent, inability to recall details of the event, and/or numbing ofgeneral responsiveness manifested as diminished interest in significantactivities, estrangement from others, restricted range of affect, orsense of foreshortened future; and symptoms of autonomic arousalincluding hypervigilance, exaggerated startle response, sleepdisturbance, impaired concentration, and irritability or outbursts ofanger. A PTSD diagnosis requires that the symptoms are present for atleast a month and that they cause clinically significant distress orimpairment in social, occupational, or other important areas offunctioning. It is contemplated that the compounds of this inventionwill be effective in treating PTSD in patients who have been diagnosedwith PTSD by administration of any of the following tests:Clinician-Administered PTSD Scale Part 2 (CAPS), the patient-ratedImpact of Event Scale (IES) (Medical Economics Company, 2002, p. 2752).It is further contemplated that the compounds of the invention will beeffective in inducing improvements in the scores of the CAPS, IES,CGI-Severity of Illness or CGI-Global Improvement tests. It is alsocontemplated that the compounds of this invention will be effective inpreventing relapse of PTSD.

In a preferred embodiment, the subject invention provides a method oftreatment or management of the following indications: depressivedisorders, anxiety disorders, eating/body weight disorders, and urinarydisorders. Examples of depressive disorders are major depressivedisorder or dysthymic disorder. Examples of anxiety disorders are panicdisorder, agoraphobia without history of panic disorder, specificphobia, social phobia, obsessive-compulsive disorder, post-traumaticstress disorder, acute stress disorder or generalized anxiety disorder.Examples of eating/body weight disorders are obesity, weight gain,bulimia, bulimia nervosa or anorexia nervosa. Examples of urinarydisorders include, but are not limited to urinary incontinenceoveractive bladder, urge incontinence, urinary frequency, urinaryurgency, nocturia or enuresis. Overactive bladder and urinary urgencymay or may not be associated with benign prostatic hyperplasia. Thisinvention provides a method of modifying the feeding behavior of asubject, which comprises administering to the subject an amount of acompound of the invention effective to decrease the consumption of foodby the subject. This invention also provides a method of treating aneating disorder in a subject, which comprises administering to thesubject an amount of a compound of the invention effective to treat theeating disorder. In an embodiment of the present invention, the eatingdisorder is obesity, bulimia, bulimia nervosa or anorexia nervosa.

The present invention further provides a method of reducing the bodymass of a subject, which comprises administering to the subject anamount of a compound of the invention effective to reduce the body massof the subject. This invention also provides a method of managingobesity in a subject in need of weight loss, which comprisesadministering to the subject an amount of a compound of the inventioneffective to induce weight loss in the subject. This invention alsoprovides a method of managing obesity in a subject who has experiencedweight loss, which comprises administering to the subject an amount of acompound of the invention effective to maintain such weight loss in thesubject. The present invention also provides a method of treatingdepression in a subject, which comprises administering to the subject anamount of a compound of the invention effective to treat the subjectsdepression. This invention also provides a method of treating anxiety ina subject, which comprises administering to the subject an amount of acompound of the invention effective to treat the subject's anxiety. Thisinvention also provides a method of treating depression and anxiety in asubject, which comprises administering to the subject an amount of acompound of the invention effective to treat the subject's depressionand anxiety. This invention also provides a method of treating majordepressive disorder in a subject, which comprises administering to thesubject an amount of a compound of the invention effective to treat thesubject's major depressive disorder. This invention also provides amethod of treating dysthymic disorder in a subject, which comprisesadministering to the subject an amount of a compound of the inventioneffective to treat the subject's dysthymic disorder. This invention alsoprovides a method of treating obsessions and compulsions in a subjectwith obsessive compulsive disorder, which comprises administering to thesubject an amount of a compound of the invention effective to treat thesubject's obsessions and compulsions. This invention also provides amethod of treating panic disorder, with or without agoraphobia, in asubject, which comprises administering to the subject an amount of acompound of the invention effective to treat the subject's panicdisorder. This invention also provides a method of treating socialanxiety disorder in a subject, which comprises administering to thesubject an amount of a compound of the invention effective to treat thesubject's social anxiety disorder. This invention also provides a methodof treating generalized anxiety disorder in a subject, which comprisesadministering to the subject an amount of a compound of the inventioneffective to treat the subject's generalized anxiety disorder. Thisinvention also provides a method of treating post-traumatic stressdisorder in a subject, which comprises administering to the subject anamount of a compound of the invention effective to treat the subject'spost-traumatic stress disorder.

It is contemplated that the compounds of this invention will beeffective in treating obesity, including weight loss and maintenance ofweight loss in patients, who have been diagnosed with obesity by the oneor more of the following measurements: an increased body mass index,increased waist circumference (an indicator of intra-adominal fat), DualEnergy X-Ray Absorptiometry (DEXA) and trucal (android) fat mass. It isfurther contemplated that the compounds of the invention will beeffective in inducing improvements in certain factors measured in thesetests. It is contemplated that the compounds of this invention will beeffective in treating urinary disorders in patients who have urge ormixed (with a predominance of urge) incontinence as evidenced by thenumber of unnecessary episodes per week, the number of unnecessarymicturitions per day and a low volume voided per micturition. It isfurther contemplated that the compounds of the invention will beeffective in inducing improvements in certain factors measured in thesetests.

The present invention also provides a method of treating a subjectsuffering from bipolar I or II disorder, schizoaffective disorder, acognitive disorder with depressed mood, a personality disorder,insomnia, hypersomnia, narcolepsy, circadian rhythm sleep disorder,nightmare disorder, sleep terror disorder or sleepwalking disorder.

The present invention provides a method of treating overactive bladderwith symptoms of urge urinary incontinence, urgency and/or frequency ina subject, which comprises administering to the subject an amount of acompound of the invention effective to treat the subject's overactivebladder. This invention also provides a method of alleviating urgeurinary incontinence in a subject suffering from overactive bladder,which comprises administering to the subject an amount of a compound ofthe invention effective to alleviate the subject's urge urinaryincontinence. This invention further provides a method of alleviatingurinary urgency in a subject suffering from overactive bladder, whichcomprises administering to the subject an amount of a compound of theinvention effective to alleviate the subjects urinary urgency.Additionally, this invention provides a method of alleviating urinaryfrequency in a subject suffering from overactive bladder, whichcomprises administering to the subject an amount of a compound of theinvention effective to alleviate the subject's urinary frequency. Thepresent invention also provides a method of treating a subject sufferingfrom a urinary disorder, which comprises administering to the subject anamount of a compound of the invention effective to treat the subject'surinary disorder. In some embodiments the urinary disorder is urinaryincontinence, overactive bladder, urge incontinence, urinary frequency,urinary urgency, nocturia or enuresis. The present invention provides amethod of alleviating the symptoms of a disorder in a subject, whichcomprises administering to the subject an amount of an MCH1 antagonisteffective to alleviate the symptoms, wherein the MCH1 antagonist is anyof the compounds of the invention.

In an embodiment of the invention, the subject is a vertebrate, amammal, a human or a canine. In another embodiment, the compound isadministered orally. In yet another embodiment, the compound isadministered in combination with food. In a preferred embodiment, thesubject invention provides a method of treatment for the followingindications: depression, anxiety, eating/body weight disorders, andurinary disorders. Examples of eating/body weight disorders are obesity,bulimia, or bulimia nervosa. Examples of urinary disorders include, butare not limited to, urinary incontinence, overactive bladder, urgeincontinence, urinary frequency, urinary urgency, nocturia, or enuresis.Overactive bladder and urinary urgency may or may not be associated withbenign prostatic hyperplasia. This invention provides a method ofmodifying the feeding behavior of a subject which comprisesadministering to the subject an amount of a compound of the inventioneffective to decrease the consumption of food by the subject. Thisinvention also provides a method of treating an eating disorder in asubject which comprises administering to the subject an amount of acompound of this invention effective to decrease the consumption of foodby the subject. In an embodiment of the present invention, the eatingdisorder is bulimia, obesity or bulimia nervosa. In an embodiment of thepresent invention, the subject is a vertebrate, a mammal, a human or acanine. In a further embodiment, the compound is administered incombination with food. The present invention further provides a methodof reducing the body mass of a subject which comprises administering tothe subject an amount of a compound of the invention effective to reducethe body mass of the subject. The present invention also provides amethod of treating a subject suffering from depression which comprisesadministering to the subject an amount of a compound of this inventioneffective to treat the subject's depression. The present inventionfurther provides a method of treating a subject suffering from anxietywhich comprises administering to the subject an amount of a compound ofthis invention effective to treat the subject's anxiety. The presentinvention also provides a method of treating a subject suffering fromdepression and anxiety which comprises administering to the subject anamount of a compound of this invention effective to treat the subject'sdepression and anxiety.

The present invention also provides a method of treating a subjectsuffering from major depressive disorder, dysthymic disorder, bipolar Iand II disorders, schizoaffective disorder, cognitive disorders withdepressed mood, personality disorders, insomnia, hypersomnia,narcolepsy, circadian rhythm sleep disorder, nightmare disorder, sleepterror disorder, sleepwalking disorder, obsessive-compulsive disorder,panic disorder, with or without agoraphobia, posttraumatic stressdisorder, social anxiety disorder, social phobia and generalized anxietydisorder. The present invention also provides a method of treating asubject suffering from a urinary disorder which comprises administeringto the subject an amount of a compound of this invention effective totreat the subject's a urinary disorder. In some embodiments, the urinarydisorder is urinary incontinence, overactive bladder, urge incontinence,urinary frequency, urinary urgency, nocturia, or enuresis.

The present invention further provides for a compound having thestructure:

wherein each R₁ is independently hydrogen; —F; —Cl; —Br; —I; —CN; —NO₂;straight chained or branched C₁-C₇ alkyl, monofluoroalkyl orpolyfluoroalkyl; straight chained or branched C₂-C₇ alkenyl; C₃-C₇cycloalkyl or C₅-C₇ cycloalkenyl; aryl; heteroaryl; —N(R₅)₂;—(CH₂)_(m)OR₅; —COR₅; —CO₂R₅; —OCOR₅; —CON(R₅)₂; —N(R₅)COR₅;—N(R₅)CON(R₅)₂; —OCON(R₅)₂ or —N(R₅)CO₂R₅;wherein R₂ and R₃ are independently hydrogen; —F; —Cl; —Br, —I; —CN;—(CH₂)_(m)OR₅; —(CH₂)_(m)SR₅; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, polyfluoroalkyl; aryl or heteroaryl, wherein the arylor heteroaryl may be substituted with one or more R₁; orwherein R₂ and R₃ together can be —(CH₂)_(p)—;wherein R₄ is hydrogen; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl or polyfluoroalkyl; C₃-C₈ cycloalkyl; —N(R₅)₂ or—(CH₂)_(m)OR₅;wherein each R₅ is independently hydrogen; aryl; heteroaryl or straightchained or branched C₁-C₇ alkyl, wherein the alkyl may be substitutedwith aryl or heteroaryl;wherein each R₆ is independently hydrogen; straight chained or branchedC₁-C₇ alkyl;wherein each R₇ is independently hydrogen; phenyl or straight chained orbranched C₁-C₇ alkyl, wherein the alkyl may be substituted with phenyl;wherein R₈ is hydrogen or straight chained C₁-C₇ alkyl;wherein R₄ and R₈ together can be —(CH₂)_(r);wherein each m is independently an integer from 0 to 5 inclusive;wherein n is an integer from 1 to 5 inclusive;wherein p is an integer from 2 to 7 inclusive;wherein q is an integer from 0 to 2 inclusive;wherein each X is independently CH or N;wherein Z is CO; SO₂ or may be absentor a pharmaceutically-acceptable salt thereof.

In one embodiment of the invention, the compound has the structure:

In another embodiment of the invention, the compound has the structure:

wherein each R₁ is independently hydrogen; —F; —Cl; —Br; —I; —CN; —NO₂;straight chained or branched C₁-C₇ alkyl, monofluoroalkyl orpolyfluoroalkyl; straight chained or branched C₂-C₇ alkenyl; C₃-C₇cycloalkyl or C₅-C₇ cycloalkenyl; aryl; heteroaryl; —N(R₅)₂;—(CH₂)_(m)OR₅; —COR₅; —CO₂R₅; —OCOR₅; —CON(R₅)₂; —N(R₅)COR₅;—N(R₅)CON(R₅)₂; —OCON(R₅)₂ or —N(R₅)CO₂R₅;wherein R₂ and R₃ are independently hydrogen; —F; —Cl; —Br; —I; —CN;—(CH₂)_(m)OR₅; —(CH₂)_(m)SR₅; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, polyfluoroalkyl; aryl or heteroaryl, wherein the arylor heteroaryl may be substituted with one or more R₁; orwherein R₂ and R₃ together can be —(CH₂)_(p)—;wherein R₄ is straight chained or branched C₁-C₇ alkyl, monofluoroalkylor polyfluoroalkyl, C₃-C₆ cycloalkyl, C₁-C₇ alkyl-C₃-C₆ cycloalkyl—N(R₅)₂ or —(CH₂)_(m)OR₅;wherein each R₅ is independently hydrogen; aryl; heteroaryl or straightchained or branched C₁-C₇ alkyl, wherein the alkyl may be substitutedwith aryl or heteroaryl;wherein each R₆ is independently hydrogen; straight chained or branchedC₁-C₇ alkyl;wherein each R₇ is independently hydrogen; phenyl or straight chained orbranched C₁-C₇ alkyl, wherein the alkyl may be substituted with phenyl;wherein each m is independently an integer from 0 to 5 inclusive;wherein n is an integer from 1 to 5 inclusive; wherein p is an integerfrom 2 to 7 inclusive; wherein q is an integer from 0 to 2 inclusive;wherein X is CH or N;or a pharmaceutically acceptable salt thereof.

In a sub-class of the invention, are the compounds wherein each R₁ isindependently hydrogen; straight chained or branched C₁-C₇ alkyl; —F;—Cl; —Br; —I; —CN; —NO₂; straight chained or branched C₁-C₄ alkyl orpolyfluoroalkyl; —(CH₂)_(m)OR₅; —COR₅; —CO₂R₅; —OCOR₅; —CON(R₅)₂;—N(R₅)COR₅ or —N(R₅)CON(R₅)₂;

wherein R₂ and R₃ are independently hydrogen; —F; —Cl; —Br; —I; —CN;—(CH₂)_(m)SR₅; straight chained or branched C₁-C₇ alkyl; aryl orheteroaryl, wherein the aryl or heteroaryl may be substituted with oneor more R₁; or

wherein R₂ and R₃ together can be —(CH₂)_(p)—;

wherein R₄ is straight chained or branched C₁-C₇ alkyl; C₃-C₆cycloalkyl; —N(R₅)₂ or —(CH₂)_(m)OR₅;

wherein each R₅ is independently hydrogen or straight chained orbranched C₁-C₃ alkyl, wherein the alkyl may be substituted with phenyl;

wherein m is 0 to 3; wherein n is 1 to 3; wherein p is an integer from 2to 5 inclusive; wherein q is 0; and wherein X is CH.

In a subclass of the invention, the compounds have the formula:

In one embodiment of the invention, the compounds having the followingstructure:

In one embodiment of the invention, each R₅ is independently hydrogen orstraight chained or branched C₁-C₃ alkyl, wherein the alkyl may besubstituted with a phenyl; R₇ is independently hydrogen or straightchained or branched C₁-C₇ alkyl; and R₄ is straight chained or branchedC₁-C₇ alkyl.

In one embodiment of the invention, each R₁ is independently hydrogen;—F; —Cl; —Br; —I or straight chained or branched C₁-C₇ alkyl; andwherein R₂ is hydrogen or straight chained or branched C₁-C₇ alkyl.

In one embodiment, n=2.

In one embodiment of the invention, R₁ is hydrogen; —F; —Cl; —Br; —I orstraight chained or branched C₁-C₇ alkyl; and

R₂ is hydrogen or straight chained or branched C₁-C₇ alkyl.

In one embodiment of the invention, R₂ is hydrogen.

In one embodiment, R₃ is OH.

In a subclass of the invention are the compounds of the formula:

In one embodiment of the invention, R₄ is C₃-C₆ cycloalkyl.

In one embodiment of the invention, each R₂ and R₃ are independentlyhydrogen; —F; —Br or straight chained or branched C₁-C₇ alkyl.

In one embodiment of the invention, R₂ and R₃ are independently hydrogenor straight chained or branched C₁-C₇ alkyl.

In one embodiment of the invention, R₂ and R₃ are independentlyhydrogen; —F or —Br.

In one embodiment of the invention, R₂ and R₃ together are —(CH₂)_(p)—;

In one embodiment of the invention, the compound has the structure:

In one embodiment of the invention, R₅ and R₇ are independently hydrogenor straight chained or branched C₁-C₇ alkyl.

In one embodiment of the invention, each R₁ is independently hydrogen;—F; —Cl; —Br; —I or straight chained or branched C₁-C₇ alkyl; andwherein R₂ is hydrogen or straight chained or branched C₁-C₇ alkyl.

In one embodiment of the invention, R₄ is straight chained or branchedC₁-C₇ alkyl.

In one embodiment of the invention, the compound has the followingstructure:

In one embodiment of the invention, the compound has the followingstructure:

In one embodiment R₂ is hydrogen or —OH; wherein R₃ is phenylsubstituted with one or more R₁ moieties; and q=0.

In one embodiment each R₅ independently hydrogen or straight chained orbranched C₁-C₃ alkyl, wherein the alkyl may be substituted with aphenyl; R₇ is independently hydrogen or straight chained or branchedC₁-C₇ alkyl; and R₄ is straight chained or branched C₁-C₇ alkyl.

In one embodiment, each R₁ is independently hydrogen; —F; —Cl; —Br; —Ior straight chained or branched C₁-C₇ alkyl.

In one embodiment, X is N.

In one embodiment, X is CR₁.

In one embodiment, R₂ is OH.

In one embodiment of the invention, the compound has the followingstructure:

In one embodiment R₃ is phenyl substituted with one or more R₁ moieties;and q=0.

In one embodiment, R₅ and R₇ are independently hydrogen or straightchained or branched C₁-C₇ alkyl; and R₄ is straight chained or branchedC₁-C₇ alkyl.

In one embodiment, R₂ is hydrogen; straight chained or branched C₁-C₇alkyl; or —OH.

In one embodiment of the invention, the compound is enantiomericallypure.

In one embodiment of the invention, the compound is diastereomericallypure.

In one embodiment of the invention, the compound is enantiomerically anddiastereomerically pure.

The present invention also provides a pharmaceutical composition thatcomprises a therapeutically effective amount of a compound of thepresent invention and a pharmaceutically acceptable carrier.

The present invention further provides a pharmaceutical composition madeby admixing a compound of the present invention and a pharmaceuticallyacceptable carrier.

The present invention also provides a process for making apharmaceutical composition comprising admixing a compound of the presentinvention and a pharmaceutically acceptable carrier.

The present invention also provides a method for treating a subjectsuffering from a disorder mediated by the MCH1 receptor comprisingadministering to the subject a therapeutically effective amount of acompound of the present invention.

In one embodiment, the therapeutically effective amount is between about0.03 and about 300 mg.

In one embodiment, the disorder is depression, anxiety, obesity or urgeincontinence.

The present invention also provides a method of treating a subjectsuffering from a disorder selected from the group consisting ofdepression, anxiety, urge incontinence or obesity comprisingadministering to the subject a therapeutically effective amount of acompound of the present invention.

The invention will be better understood from the Experimental Detailswhich follow. However, one skilled in the art will readily appreciatethat the specific methods and results discussed are merely illustrativeof the invention as described more fully in the claims which followthereafter.

Experimental Section

I. Synthetic Methods for Examples

General Methods: All reactions (except for those done by parallelsynthesis reaction arrays) were performed under an Argon atmosphere andthe reagents, neat or in appropriate solvents, were transferred to thereaction vessel via syringe and cannula techniques. The parallelsynthesis reaction arrays were performed in vials (without an inertatmosphere) using J-KEM heating shakers (Saint Louis, Mo.). Anhydroussolvents were purchased from Aldrich Chemical Company and used asreceived. The compounds described herein were named using ACD/Nameprogram (version 4.0, Advanced Chemistry Development Inc., Toronto,Ontario, M5H2L3, Canada). The ¹H NMR spectra were recorded at 400 MHzusing a Bruker Avance spectrometer with tetramethylsilane as internalstandard. Splitting patterns were designated as follows: s=singlet;d=doublet; t=triplet; q=quartet; quintet; sextet; septet; br=broad;m=multiplet. Elemental analyses were performed by Robertson MicrolitLaboratories, Inc. Mass spectra were obtained on a Platform II (Fisons)or Quattro Micro (Micromass) spectrometer with electrospray (ESMS)ionization and MH⁺ is reported. Thin-layer chromatography (TLC) wascarried out on glass plates precoated with silica gel 60 F₂₅₄ (0.25 mm,EM Separations Tech.). Preparative thin-layer chromatography was carriedout on glass sheets precoated with silica gel GF (2 mm, Analtech). Flashcolumn chromatography was performed on Merck silica gel 60 (230-400mesh). Melting points (mp) were determined in open capillary tubes on aMel-Temp apparatus and are uncorrected.

The examples described in the experimental section are merelyillustrative of the methods used to synthesize MCH1 antagonists. A moredetailed description of each reaction is represented by the proceduresfollowing the schemes. Additional compounds of the invention can beobtained by the general synthetic procedures described herein or byincorporating variations into these methods. The definitions of thevariables depicted in the below-identified schemes are defined in theSummary of the Invention. For example, the variable R₄ may be straightchained or branched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl,C₃-C₆ cycloalkyl, C₁-C₇ alkyl-C₃-C₆-cycloalkyl; —N(R₅)₂ or—(CH₂)_(m)OR₅. Additionally, for clarity purposes, the number ofmoieties (R₁) off phenyl have been limited in number to one.

General Procedure for Piperidine Side Chain Synthesis (Scheme 1):

TERT-BUTYL 4-{[(TRIFLUOROMETHYL)SULFONYL]OXY}-3,6-DIHYDRO-1(2H)-PYRIDINECARBOXYLATE: n-Butyl lithium (17.6 mL, 44.2 mmol, 2.5 M in hexanes) wasadded to a solution of diisopropyl amine (96.2 mL, 44.2 mmol) in 40 mLof dry THF at 0° C. and the resulting mixture was stirred for 20minutes. The reaction mixture was cooled to −78° C. and tert-butyl4-oxo-1-piperidinecarboxylate (Aldrich Chemical Company, 40.0 mmol) inTHF (40 mL) was added dropwise to the reaction mixture, which was thenstirred for 30 minutes. Tf₂NPh (42.0 mmol, 15.0 g) in THF (40 mL) wasadded dropwise to the reaction mixture and stirred at 0° C. overnight.The reaction mixture was concentrated in vacuo, re-dissolved inhexanes:EtOAc (9:1), passed through a plug of alumina and the aluminaplug was washed with hexanes:EtOAc (9:1). The combined extracts wereconcentrated to yield 16.5 g of the desired product that wascontaminated with some starting Tf₂NPh.

TERT-BUTYL 4-(3-AMINOPHENYL)-3,6-DIHYDRO-1(2H)-PYRIDINECARBOXYLATE: Adegassed mixture of 2 M aqueous Na₂CO₃ solution (4.2 mL), tert-butyl4-{[(trifluoromethyl)sulfonyl]oxy}3,6-dihydro-1 (2H)-pyridinecarboxylate(0.500 g, 1.51 mmol), 3-aminophenylboronic acid hemisulfate (0.393 g,2.11 mmol), lithium chloride (0.191 g, 4.50 mmol) andtetrakis-triphenylphosphine palladium (0) (0.080 g, 0.075 mmol) indimethoxyethane (5 mL) was heated at reflux temperature for 3 hoursunder an inert atmosphere. The organic layer of the cooled reactionmixture was separated and the aqueous layer was washed with ethylacetate (3×50 mL). The combined organic solutions were dried andconcentrated in vacuo. The crude product was chromatographed (silica,hexanes:EtOAc:dichloromethane=6:1:1 with 1% added isopropylamine) togive 0.330 g of the desired product in 81% yield. ESMS m/e: 275.2(M+H)⁺.

TERT-BUTYL 4-[3-(AMINO)PHENYL]-1-PIPERIDINECARBOXYLATE: A mixture of3.10 g of tert-butyl4-(3-aminophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate (11.3 mmol) and1.0 g of 10% Pd/C in 200 mL of ethanol was hydrogenated at roomtemperature using the balloon method for 2 days. The reaction mixturewas filtered through Celite and washed with ethanol. The combinedethanol extracts were concentrated in vacuo and the residue waschromatographed on silica(dichloromethane:methanol:isopropylamine=95:5:1) to give 2.63 g of thedesired product (84%): ESMS m/e: 277.2 (M+H)⁺.

TERT-BUTYL 4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINECARBOXYLATE. Into asolution of 14.6 g (52.6 mmol) of tert-butyl4-[3-(amino)phenyl]-1-piperidinecarboxylate and 14.7 mL (105 mmol) oftriethylamine in 120 mL THF at 0° C. was slowly added 4.5 mL (63.1 mmol)of acetyl chloride. The reaction mixture was stirred at room temperaturefor 2 hours and concentrated in vacuo. The residue was dissolved inCH₂Cl₂ and washed with H₂O, followed by brine. The organic layer wasdried over MgSO₄ and concentrated in vacuo to give 16.6 g (52.1 mmol,99%) of desired product: ¹H NMR (400 MHz, CDCl₃) δ 7.41-7.20 (m, 3H),6.94 (d, 1H, J=7.5 Hz), 4.21 (m, 2H), 2.75 (m, 2H), 2.62 (m, 1H), 2.16(s, 3H), 1.78 (m, 2H), 1.56 (m, 2H), 1.48 (s, 9H).

N-[3-(4-PIPERIDYL)PHENYL]ACETAMIDE: A solution of HCl in dioxane (4N, 5mL) was added to tert-butyl4-[3-(acetylamino)phenyl]-1-piperidinecarboxylate (660 mg) in drydichloromethane (15 mL). The reaction mixture was stirred at roomtemperature overnight and concentrated in vacuo, giving the HCl salt ofthe desired product (550 mg): ¹H NMR (400 MHz, CDCl₃) δ 2.02 (d, J=13.2Hz, 2H), 2.11-2.45 (m, 5H), 2.67-2.77 (m, 1H), 3.00-3.10 (m, 2H), 3.51(d, J=10.5 Hz, 2H), 6.94 (d, J=7.5 Hz, 1H), 7.20-7.46 (m, 3H), 7.60 (s,1H).

TERT-BUTYL 4-[3-(ISOBUTYRYLAMINO)PHENYL]-3,6-DIHYDRO-1(2H)-PYRIDINECARBOXYLATE: Anal. Calc. for C₂₀H₂₈N₂O₃+0.175 CHCl₃: C, 66.33; H, 7.77;N, 7.67. Found: C, 66.20; H, 7.41; N, 7.88. and TERT-BUTYL4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINECARBOXYLATE: ESMS m/e: 347.2(M+H)⁺. These intermediates were synthesized as illustrated by themethods above.

2-METHYL-N-[3-(4-PIPERIDINYL)PHENYL]PROPANAMIDE: Into a stirred solutionof 2.20 g (6.50 mmol) of tert-butyl4-[3-(isobutyrylamino)phenyl]-1-piperidinecarboxylate in 100 ml of1,4-dioxane at 0° C. was bubbled HCl gas for 10 minutes. The reactionmixture was allowed to warm to room temperature and the bubbling of theHCl gas was continued for 1 hour. The solvent was removed in vacuo, theresidue was dissolved in 50 mL of water and was basified to pH=13 byaddition of KOH pellets. The aqueous solution was extracted with 3×80 mLof dichloromethane. The combined organic extracts were dried (MgSO₄),filtered and concentrated in vacuo. The residue was purified by columnchromatography (silica, 9:1:0.1=dichloromethane:methanol:isopropylamine) to afford 0.700 g (46% yield) of the desired product ESMS m/e:247.2 (M+H)⁺.

Using the methods described above, the following intermediates werefurther synthesized. TERT-BUTYL4-[3-(PROPIONYLAMINO)PHENYL]-1-PIPERIDINECARBOXYLATE: ESMS m/e: 333.4(M+H)⁺; N-[3-(4-PIPERIDINYL)PHENYL]PROPANAMIDE: ESMS m/e: 233.1 (M+H)⁺.

TERT-BUTYL4-{3-[(CYCLOPROPYLCARBONYL)AMINO]PHENYL}1-PIPERIDINECARBOXYLATE: ESMS m/e: 345.5 (M+H)⁺; N-[3-(4-PIPERIDINYL)PHENYL]CYCLOPROPANECARBOXAMIDE: ESMS m/e: 245.0 (M+H)⁺;N-[3-(4-PIPERIDINYL)PHENYL]BUTANAMIDE: ESMS m/e: 247.3 (M+H)⁺;N,N-DIMETHYL-N′-[3-(4-PIPERIDINYL) PHENYL]UREA: ESMS m/e: 248.2 (M+H)⁺;ISOPROPYL 3-(4-PIPERIDINYL)PHENYL CARBAMATE: ESMS m/e: 263.4 (M+H)⁺;BENZYL 3-(4-PIPERIDINYL)PHENYLCARBAMATE: ESMS m/e: 311.3 (M+H)⁺;2-METHYL-N-[4-(4 PIPERIDINYL)PHENYL]PROPANAMIDE: ESMS m/e: 247.1 (M+H)⁺;N-[4-(4 PIPERIDINYL)PHENYL]BUTANAMIDE: ESMS m/e: 247.2 (M+H)⁺.

General Procedure for the Synthesis of 4-Aryl Piperidines (Scheme 2)

TERT-BUTYL4-(4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)-3,6-DIHYDRO-1(2H)-PYRIDINECARBOXYLATE:To a 50-mL RB-flask, charged with bis(pinacolato)diboron (422 mg, 1.66mmol), KOAc (444 mg, 4.53 mmol), PdCl₂dppf (37.0 mg, 3.00 mol %) anddppf (25.0 mg, 3.00 mol %) was added a solution of tert-butyl4-{[(trifluoromethyl)sulfonyl]oxy}3,6-dihydro-1(2H)-pyridinecarboxylate(500 mg, 1.51 mmol) in 1,4-dioxane (10.0 mL) at room temperature underargon. The mixture was heated at 80° C. overnight. After cooling to roomtemperature, the mixture was filtered through Celite and the Celite waswashed with EtOAc (3×20 mL). The filtrates were concentrated in vacuo.The resulting residue was dissolved in EtOAc and washed with H₂O andbrine, dried over MgSO₄, filtered and concentrated in vacuo. The crudeproduct was purified by flash chromatography (1:9 EtOAc:hexane) to givetert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2M-pyridinecarboxylate(355 mg, 76%): ¹H NMR (400 MHz, CDCl₃) δ 6.60-6.34 (br, 1H), 4.06-3.86(br, 2H), 3.55-3.34 (br, 2H), 2.35-2.09 (br, 2H), 1.46 (s, 9H), 1.26 (s,12H); ESMS m/e: 310.4 (M+H)⁺.

Method A (Scheme 2)

N-(3-BROMO-4-METHYLPHENYL)-2-METHYLPROPANAMIDE: Into a solution of 1.0 g(5.40 mmol) of 3-bromomethylaniline and 0.91 mL (6.50 mmol) oftriethylamine in 10 mL THF at 0° C. was slowly added 0.68 mL (6.50 mmol)of 2-methylpropanoyl chloride. The reaction mixture was stirred at roomtemperature for 2 hours and concentrated in vacuo. The residue wasdissolved in CH₂Cl₂ and washed with H₂O, followed by brine. The organiclayer was dried over MgSO₄ and concentrated in vacuo to give 1.37 g(5.35 mmol, 99%) of the desired product: ESMS m/e: 255.9 (M+H)⁺.

Using the methods described above, the following intermediates werefurther synthesized. N-(3-BROMO-2-METHYLPHENYL)-2-METHYLPROPANAMIDE:ESMS m/e: 255.9 (M+H)⁺.

N-(6-BROMO-2-PYRIDINYL-2-METHYLPROPANAMIDE: ESMS m/e: 242.8 (M+H)⁺.

TERT-BUTYL4-[5-(ISOBUTYRYLAMINO)-2-METHYLPHENYL]-3,6-DIHYDRO-1(2H)-PYRIDINECARBOXYLATE: To a 50-mL RB-flask containing tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate(500 mg, 1.62 mmol), K₂CO₃ (670 mg, 4.86 mmol) and PdCl₂dppf (0.190mmol, 155 mg) was added a solution ofN-(3-bromo-4-methylphenyl)-2-methylpropanamide (415 mg, 1.62 mmol) inDMF (10.0 mL) at room temperature under argon. The mixture was heated to80° C. under argon overnight. After cooling to room temperature, themixture was filtered through Celite and the Celite was washed with EtOAc(3×20 mL). The filtrates were washed with H₂O (20 mL), brine (20 mL),dried over MgSO₄, filtered and concentrated in vacuo. The crude materialwas purified flash chromatography (20% EtOAc/hexane) to give tert-butyl4-[5-(isobutyrylamino)-2-methylphenyl]-3,6-dihydro-1(2H)-pyridinecarboxylate(360 mg, 62%): ESMS m/e: 303.0 (M-56+H)⁺.

TERT-BUTYL 4-[5-(ISOBUTYRYLAMINO)-2-METHYLPHENYL]-1-PIPERIDINECARBOXYLATE: A mixture of tert-butyl4-[5-(isobutyrylamino)-2-methylphenyl]-3,6-dihydro-1(2H)-pyridinecarboxylate(335 mg, 0.93 mmol) and 10% Pd/C (35.0 mg) in EtOH (20.0 mL) washydrogenated at room temperature overnight using the hydrogen balloonmethod. The reaction mixture was filtered through Celite and washed withethanol (3×10 mL). The combined extracts were concentrated in vacuo toafford tert-butyl4-[5-(isobutyrylamino)-2-methylphenyl]1-piperidinecarboxylate (335 mg,100%): ESMS m/e: 361.4 (M+H)⁺.

2-METHYL-N-[4-METHYL-3-(4-PIPERIDINYL)PHENYL] PROPANAMIDE: Into asolution of tert-butyl4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidinecarboxylate (335 mg,0.930 mmol) in CH₂Cl₂ (10.0 mL) was added TFA (10.0 mL) at roomtemperature. The reaction mixture was stirred for 2 h and concentratedin vacuo. The residue was dissolved in 20 mL of CHCl₃/i-PrOH (3:1) andwas basified with 5% KOH solution (10 mL). The aqueous layer wasextracted with

CHCl₃/i-PrOH (3:1, 3×10 mL). The combined organic extracts were washedwith brine, dried over MgSO₄, filtered and concentrated in vacuo to give2-methyl-N-[4-methyl-3-(4-piperidinyl)phenyl]propanamide (190 mg, 78%):ESMS m/e: 261.0 (M+H)⁺.

Using the methods described above, the following intermediates werefurther synthesized.2-METHYL-N-[2-METHYL-3-(4-PIPERIDINYL)PHENYL]PROPANAMIDE: ESMS m/e:261.3 (M+H)⁺. 2-METHYL-N-[6-(4-PIPERIDINYL)-2-PYRIDINYL]PROPANAMIDE:ESMS m/e: 248.1 (M+H)⁺.

Method B (Scheme 2)

TERT-BUTYL 4-(2-METHOXY-5-NITROPHENYL)-3,6-DIHYDRO-1(2H)-PYRIDINECARBOXYLATE: To a 250-mL RB-flask containing tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate(3.09 g, 10.0 mmol), K₂CO₃ (4.14 g, 30.0 mmol) and PdCl₂dppf (419 mg)was added a solution of 2-bromo-4-nitroanisole (2.30 g, 10 mmol) in DMF(10.0 mL) at room temperature under argon. The mixture was heated to 80°C. under argon overnight. After cooled to room temperature, water (500mL) was added to the mixture. The aqueous layer was extracted with EtOAc(2×200 mL) and the combined organic extracts were dried over K₂CO₃,filtered and concentrated in vacuo. The crude material was purified onflash chromatography (20% EtOAc/hexane) to give tert-butyl4-(2-methoxy-5-nitrophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate (1.51g, 46%): ESMS m/e: 334.9 (M+H)⁺.

TERT-BUTYL 4-[5-AMINO-2-METHOXYPHENYL]-1-PIPERIDINECARBOXYLATE: Asolution of tert-butyl4-(2-methoxy-5-nitrophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate (1.30g, 3.90 mmol) and 10% Pd/C (200.0 mg) in MeOH:EtOAc (1:4, 100 mL) washydrogenated at room temperature for 72 h using the hydrogen balloonmethod. The reaction mixture was filtered through Celite and washed withethanol (3×100 mL). The combined organic filtrates were concentrated invacuo to afford tert-butyl4-[5-amino-2-methoxyphenyl]-1-piperidinecarboxylate (1.00 g, 84%): ESMSm/e: 307.2 (M+H)⁺.

tert-Butyl4-[5-(ISOBUTYRYLAMINO)-2-METHOXYPHENYL]-1-PIPERIDINECARBOXYLATE: ¹H NMR(400 MHz, CDCl₃) δ 7.39 (dd, 1H, J=8.8, 2.8 Hz), 7.25 (br, 1H), 6.80 (d,1H, J=8.4 Hz), 4.23 (br, 2H), 3.80 (s, 3H), 3.07 (tt, 1H, J=11.8, 4.1Hz), 2.89-2.73 (m, 2H), 2.49 (septet, 1H, J=6.7 Hz), 1.77 (d, 2H, J=11.6Hz), 1.64-1.52 (m, 3H), 1.48 (s, 9H), 1.25 (d, 6H, J=6.8 Hz).

Using the methods described above, the following additionalintermediates were synthesized.N-[4-METHOXY-3-(4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: ESMS m/e:277.2 (M+H)⁺. N-[4-FLUORO-3-(4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:ESMS m/e: 265.2 (M+H)⁺.N-[2-FLUORO-5-(4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: ESMS m/e:265.4 (M+H)⁺. N-[4-FLUORO-3-(4-PIPERIDINYL)PHENYL]BUTANAMIDE: ESMS m/e:265.2 (M+H)⁺. N-[2-FLUORO-5-(4-PIPERIDINYL)PHENYL]BUTANAMIDE: ESMS m/e:265.4 (M+H)⁺. N-[4-METHOXY-3-(4-PIPERIDINYL)PHENYL]BUTANAMIDE: ¹H NMR(400 MHz, CD₃OD) δ 7.34 (dd, 1H, J=8.1, 3.3 Hz), 7.25 (d, 1H, J=3.3 Hz),6.82 (d, 1H, J=8.1 Hz), 3.76 (s, 3H), 3.10-2.92 (m, 4H), 2.66 (dt, 2H,J=12.6, 2.6 Hz), 2.64-2.56 (m, 1H), 2.27 (t, 2H, J=7.4 Hz), 1.76-1.44(m, 6H), 0.95 (t, 3H, J=7.4 Hz).

N-[2-HYDROXY-5-(4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: Prepared bythe procedure forN-[4-methoxy-3-(4-piperidinyl)phenyl]-2-methylpropanamide usingtert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H-pyridinecarboxylateand 4-bromo-2-nitrophenol and acylating with isobutyryl chloride: ESMSm/e: 263.4 (M+H)⁺.

General Procedures for N-(n-Aminoalkyl)Piperidine Synthesis (Scheme 3)

Method A (Scheme 3)

TERT-BUTYL 3-BROMOPROPYLCARBAMATE: A solution of 3-bromopropylaminehydrobromide (10.9 g, 49.8 mmol), BOC₂O (11.4 g, 52.3 mmol) and K₂CO₃(20.6 g, 149.4 mmol) in ethanol (100 ml) were stirred at roomtemperature overnight. The precipitated salts were removed by filtrationand the filtrate was concentrated in vacuo. The residue was dissolved indichloromethane and washed with water, followed by brine. The organiclayer was dried over MgSO₄ and concentrated in vacuo to give 11.2 g(46.9 mmol, 94%) of the desired product: ¹H NMR (400 MHz, CDCl₃) δ 5.07(br, 1H), 3.31 (t, 2H, J=6.6 Hz), 3.12 (apparent br q, 2H, J=6.0 Hz),1.92 (quintet, 2H, J=6.6 Hz), 1.30 (s, 9H).

TERT-BUTYL 3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYLCARBAMATE: Amixture of N-[3-(4-piperidyl)phenyl]acetamide (550 mg, 2.1 mmol),tert-butyl 3-bromopropylcarbamate (550 mg, 2.3 mmol), K₂CO₃ (1.10 g, 8.9mmol), diisopropylethyl amine (1.50 mL) and a few crystals of KI indioxane (20 mL) was heated at reflux temperature for 2 days. Theprecipitated salts were removed by filtration, the filtrate wasconcentrated in vacuo and the crude product was chromatographed onsilica to give the desired product (340 mg; 43%): ESMS m/e: 376.2(M+H)⁺.

N-{3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]PHENYL}ACETAMIDE: Trifluoroaceticacid (1.0 mL) was added to a solution of tert-butyl3-{4-[3-(acetylamino)phenyl]-1-piperidinyl} propylcarbamate (340 mg) indry dichloromethane (10 mL) and the reaction mixture was stirred at roomtemperature for 5 h. The reaction mixture was basified to pH 12 byaddition of a 10% aqueous solution of KOH and then the dichloromethanewas removed in vacuo. The aqueous layer was frozen and lyophilized togive a solid, which was extracted with methanol. Removal of the solventgave the desired product (120 mg) as an oil: ¹H NMR (400 MHz, CDCl₃) δ7.48 (m, 1H), 7.38 (d, 1H, J=7.7 Hz), 7.24 (t, 1H, J=7.7 Hz), 6.99 (d,1H, J=7.7 Hz), 3.11 (d, 2H, J=11.6 Hz), 2.84 (t, 2H. J=6.6 Hz),2.59-2.52 (m, 1H), 2.50 (t, 2H, J=6.6 Hz), 2.18-2.09 (m, 2H), 2.13 (s,3H), 1.90-1.72 (m, 6H).

Using the methods described above, the following additionalintermediates were synthesized.N-{3-[1-(3-AMINOPROPYL)-PIPERIDINYL]PHENYL}BUTANAMIDE. ESMS m/e: 304.3(M+H)⁺. N{3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]METHYLPHENYL}2-METHYLPROPANAMIDE. ESMS m/e: 318.3 (M+H)⁺.N-{3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]-4-FLUOROPHENYL}-2-METHYLPROPANAMIDE. ESMS m/e: 322.4 (M+H)⁺.N-{6-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]-2-PYRIDINYL}-2-METHYLPROPANAMIDE.ESMS m/e: 305.2 (M+H)⁺.N-{5-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]-2-FLUOROPHENYL}-2-METHYLPROPANAMIDE.ESMS m/e: 322.4 (M+H)⁺.N-{5-[1-(3-AMINOPROPYL)-2-PIPERIDINYL]-2-FLUOROPHENYL}BUTANAMIDE. ESMSm/e: 322.3 (M+H)⁺.

Method B (Scheme 3)

Step 1: A mixture of piperidine 1 (1.00 eq, 0.0226 mmol),N-(n-bromoalkyl)phthalimide (1.50 eq, 0.0338 mmol), Bu₄NI (200 mg) anddiisopropylethylamine (5.00 eq, 0.113 mmol) in dioxane (200 mL) washeated at 99° C. for 24 h. The reaction was monitored by TLC analysis(95:5 CH₂Cl₂:methanol). If necessary, additional 0.0113 mmol of theappropriate bromoalkylphthalimide was added to the reaction mixture andheating was continued for an additional 48 h. The reaction mixture wascooled to room temperature, the ammonium salts were filtered out and thesolvent was removed under reduced pressure. The crude product waschromatographed (silica) to give the desiredN-(n-phthalimidoalkyl)piperidine 2.

Step 2: Deprotection of the N-(n-phthalimidoalkyl)piperidine from step 1was accomplished by heating a solution of phthalimide-protected amine 2with excess hydrazine hydrate (10 eq) in ethanol (0.5-1.0 M) at 90° C.for 4 h. The reaction mixture was monitored by TLC to completion. Uponcompletion of the reaction, the mixture was cooled to room temperature,the insoluble by-products were removed by filtration through Celite andthe filtrate was concentrated in vacuo. The crude product waschromatographed (dichloromethane-methanolisopropylamine) to give thedesired N-(n-aminoalkyl)piperidine 3.

Using the methods described above, the following additionalintermediates were synthesized.N-(3-{1-[2-(1,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)ETHYL]-4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE.ESMS m/e: 420.2 (M+H)⁺.N-(3-{1-[3-(1,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)PROPYL]-4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE:ESMS m/e: 434.4 (M+H)⁺.N-(3-{1-[4-(1,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)BUTYL)-4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE:ESMS m/e: 448.4 (M+H)⁺.N-(3-{1-[5-(1,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)PENTYL]-4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE.ESMS m/e: 462.4 (M+H)⁺.N-(3-{1-[6-(1,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)HEXYL]-4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE:ESMS m/e: 476.4 (M+H)⁺.

N-{3-[1-(2-AMINOETHYL)-4-PIPERIDINYL]PHENYL}-2-METHYLPROPANAMIDE:Prepared according to step 2 of Method B (Scheme 3) usingN-(3-{1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-4-piperidinyl}phenyl)-2-methylpropanamideand hydrazine hydrate; ESMS m/e: 290.2 (M+H)⁺.

Using the methods described above, the following additionalintermediates were synthesized.N-{3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]PHENYL}2-METHYLPROPANAMIDE: ESMSm/e: 304.1 (M+H)⁺.N-{3-[1-(4-AMINOBUTYL)-4-PIPERIDINYL]PHENYL}-2-METHYLPROPANAMIDE: ESMSm/e: 318.2 (M+H)⁺.N-{3-[1-(5-AMINOPENTYL)-4-PIPERIDINYL]PHENYL}-2-METHYLPROPANAMIDE: ESMSm/e: 332.2 (M+H)⁺.N-{3-[1-(6-AMINOHEXYL)-4-PIPERIDINYL]PHENYL}-2-METHYLPROPANAMIDE: ESMSm/e: 346.3 (M+H)⁺.N-{3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]PHENYL}PROPANAMIDE: ¹H NMR (400MHz, CDCl₃) δ 7.37-7.29 (m, 2H), 7.14 (t, 1H, J=7.9 Hz), 6.90 (d, 1H,J=7.9 Hz), 3.27 (s, 2H), 3.06-2.97 (m, 2H), 2.63 (t, 2H, J=6.8 Hz),2.50-2.26 (m, 6H), 2.04 (dt, 2H, J=12.1, 2.7 Hz), 1.81 (m, 3H),1.80-1.60 (m, 6H). N-{3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]PHENYL}CYCLOPROPANECARBOXAMIDE: ESMS m/e: 302.3 (M+H)⁺.N-{3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]PHENYL}-2,2-DIMETHYLPROPANAMIDE:ESMS m/e: 318.3 (M+H)⁺.N-{3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]PHENYL}-3-METHYL BUTANAMIDE: ESMSm/e: 318.3 (M+H)⁺.N-{3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]PHENYL}-3,3-DIMETHYLBUTANAMIDE:ESMS m/e: 332.3 (M+H)⁺.

Using the methods described above, the following additionalintermediates were synthesized.N′-{3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]PHENYL}-N,N-DIMETHYLUREA: ¹H NMR(400 MHz, CD₃OD) δ 7.36 (s, 1H), 7.32-7.25 (m, 1H), 7.21 (t, 1H, J=7.9Hz), 6.92 (d, 1H, J=7 Hz), 3.33 (s, 6H), 3.17-3.07 (m, 2H), 2.75 (t, 2H,J=6.9), 2.58-2.44 (m, 3H), 2.14 (dt, 2H, J=11.8, 2.7 Hz), 1.93-1.67 (m,8H). ISOPROPYL 3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL] PHENYLCARBAMATE: ¹HNMR (400 MHz, CDCl₃) δ 7.20 (broad s, 1H), 7.16 (d, 1H, J=5.3 Hz), 7.08(t, 1H, J=8.3 Hz), 6.80 (d, 1H, J=7.4 Hz), 4.89-4.79 (m, 1H), 3.21(quintet, 1H, J=1.6 Hz), 3.03-2.95 (m, 2H), 2.61 (t, 2H, 6.8 Hz),2.46-2.31 (m, 3H), 2.01 (dt, 2H, J=11.7, 2.8 Hz), 1.78-1.57 (m, 7H),1.19 (d, 6H, J=6.2 Hz). BENZYL3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]PHENYLCARBAMATE: ¹H NMR (400 MHz,CDCl₃) δ 7.60-7.30 (m, 9H), 7.08 (dt, 1H, J=7.5, 1.4 Hz), 5.34 (s, 2H),4.09 (quintet, 1H, J=5.7 Hz), 3.30-3.10 (m, 4H), 2.65 (t, 2H, J=7.8 Hz),2.28 (dt, 2H, J=12, 1.4 Hz), 2.07-1.85 (m, 7H).N-{3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]-4-METHOXYPHENYL}-2-METHYLPROPANAMIDE:ESMS m/e: 334.6 (M+H)⁺.N-{3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]-4-METHOXYPHENYL}BUTANAMIDE: ¹HNMR (400 MHz, CD₃OD) δ 7.46-7.57 (m, 1H), 6.97 (s, 1H), 6.77 (d, 1H,J=8.8 Hz), 3.88-3.80 (m, 2H), 3.78 (s, 3H), 3.12-2.74 (m, 4H), 2.46 (t,2H, J=6.6 Hz), 2.39 (t, 2H, J=7.3 Hz), 2.07-1.94 (m, 2H), 1.87-1.44 (m,9H), 1.02 (t, 3H, J=7.4 Hz).N-{5-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]-2-HYDROXYPHENYL}-2-METHYLPROPANAMIDE:¹H NMR (400 MHz, CD₃OD) δ 8.12-8.08 (m, 1H), 7.70-7.66 (m, 2H), 7.44 (d,1H, J=2.2 Hz), 2.79-2.55 (m, 3H), 2.39-2.28 (m, 3H), 2.26 (d, 2H, J=11.6Hz), 1.98 (dt, 2H, J=12, 2.5 Hz), 1.74-1.53 (m, 6H), 1.11 (d, 6H, J=6.8Hz).

General Procedure for Scheme 4

Step 1

N-(3-{1-[(3R)-3-HYDROXY-3-PHENYLPROPYL]-4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE:Into a 25-mL RB-flask was added (R)-(+)-3-chloro-1-phenyl-1-propanol(0.545 g, 3.19 mmol, 99% ee, Aldrich Chemical Co.),2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (0.748 g, 3.04 mmol),potassium carbonate (0.420 g, 3.04 mmol), sodium iodide (0.684 g, 4.56mmol) and DMF (6.0 mL) at room temperature. After stirring at 100° C.for 3 hrs, TLC showed that the reaction was complete. The reactionmixture was cooled to room temperature and poured into water (50 mL) andthe aqueous layer was extracted with methylene chloride (3×20 mL). Thecombined organic extracts were washed with brine (20 mL), dried overNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby flash chromatography (1:1=hexane:ethyl acetate with 1%isopropylamine) to afford the desired product (1.09 g, 94% yield) as alight-yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 8.10 (s, 1H), 7.46-7.35(m, 6H), 7.27 (m, 2H), 6.98 (apparent d, 1H, J=7.6 Hz), 5.02 (apparentdd, 1H, J=4.4, 8.1 Hz), 3.18 (apparent dd, 2H, J=2.5, 12.5 Hz), 2.74 (m,2H), 2.50 (m, 2H), 2.30-2.10 (m, 6H), 1.80 (m, 2H), 1.25 (d, 6H, J=7.1Hz); ESMS m/e: 381.2 (M+H)⁺.

Step 2: See general coupling conditions in Schemes 8-10.

General Procedure for Scheme 5

Step 1:

2-[(1S)-3-CHLORO-1-PHENYLPROPYL]-1H-ISOINDOLE-1,3(2H)-DIONE: Preparedaccording to the general procedure described in Srebnik, M.;Ramachandran, P. V.; Brown, H. C. J. Org. Chem. 1988, 53, 2916-2920. Amixture of phthalimide (0.147 g, 1.0 mmol),(R)-(+)-3-chloro-1-phenyl-1-propanol (0.171 g, 1.0 mmol),triphenylphosphine (0.262 g, 1.0 mmol) and diethyl azodicarboxylate(0.174 g, 1.0 mmol) in 5.0 mL of THF was stirred at room temperature for24 h. The reaction mixture was concentrated in vacuo. The residue waswashed with pentane (3×50 mL) and the combined pentane extracts wereconcentrated and chromatographed (silica, hexanes:EtOAc=8:1 as theeluent) to give the desired product (0.121 g, 50%) as a yellow solid: ¹HNMR (400 MHz, CDCl₃) δ 7.82 (apparent dd, 2H, J=2.9 Hz), 7.70 (apparentdd, 2H, J=2.9 Hz), 7.56 (m, 2H), 7.39-7.27 (m, 3H), 5.64 (apparent dd,1H, J=7.0, 9.2 Hz), 3.57 (m, 2H), 3.05 (m, 1H), 2.82 (septet, 1H, J=7.0Hz); ESMS m/e: 300.1 (M+H)⁺.

Step 2:

N-(3-{1-[(3S)-3-(1,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)-3-PHENYLPROPYL]-4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE:A mixture of potassium carbonate (29.2 mg, 0.211 mmol), sodium iodide(47.5 mg, 0.317 mmol), 2-methyl-N-[3-(4 piperidinyl)phenyl]propanamide(51.8 mg, 0.211 mmol) and2-[(1S)-3-chloro-1-phenylpropyl]-1H-isoindole-1,3(2H)-dione (63.1 mg,0.211 mmol) in DMF (5.0 mL) was stirred at 100° C. for 3 hrs, at whichtime TLC indicated that the reaction was complete. The reaction mixturewas cooled to room temperature, poured into water (50 mL) and theaqueous layer was extracted with methylene chloride (3×30 mL). Thecombined organic extracts were washed with brine (30 mL), dried overMgSO₄ and concentrated under reduced pressure. The crude product waspurified by preparative TLC [2.5% NH₃ (2.0 M in methanol) in CHCl₃] togive the desired product (74.1 mg, 77%) as a thick oil: ¹H NMR (400 MHz,CDCl₃) δ 7.83 (apparent dd, 2H, J=2.9 Hz), 7.69 (apparent dd, 2H, J=2.9Hz), 7.56 (apparent dt, 3H, J=2.9, 7.3 Hz), 7.33 (m, 4H), 7.21 (t, 1H,J=7.8 Hz), 7.09 (s, 1H), 6.81 (apparent d, 1H, J=7.8 Hz), 5.49 (apparentdd, 1H, J=5.5, 9.5 Hz), 2.98 (d, 1H, J=9.5 Hz), 2.87 (m, 2H), 2.50(septet, 1H, J=6.7 Hz), 2.40-2.35 (m, 4H), 1.94 (m, 2H), 1.70-1.50 (m,4H), 1.25 (d, 6H, J=7.9 Hz); ESMS m/e: 510.4 (M+H)⁺.

Step 3: See Scheme 3/Method B for general deprotection conditions.

Step 4: See general coupling conditions in Schemes 8-10.

General Procedure for Scheme 6

BIS(4-FLUOROPHENYL)ACETIC ACID. Fluorobenzene (13.6 g, 0.142 mol) andglyoxylic acid monohydrate (2.35 g, 0.0255 mol) were dissolved in warmacetic acid (30.0 mL). The mixture was cooled in an ice/water bath andconcentrated sulfuric acid (20.0 mL) was added dropwise over 0.5 h. Theresulting thick red suspension was stirred at 80° C. for 12 h and thencooled to room temperature. Water (300 mL) was added and the pH wasadjusted to 3 with potassium hydroxide pellets and 10% KOH solution. Theaqueous solution was extracted with ethyl acetate (3×100 mL) and thecombined organic extracts were washed with brine (100 mL) and dried oversodium sulfate, filtered and concentrated in vacuo to give the desiredproduct (5.18 g, 82%) as a red solid, which was used in the subsequentstep without further purification: ¹H NMR (400 MHz, CD₃OD) δ 9.45 (br s,1H), 7.31-7.25 (m, 4H), 7.06-7.0 (m, 4H), 5.01 (s, 1H).

General Procedure for Scheme 7

BIS(4-METHYLPHENYL)ACETIC ACID. To a 250 mL RB-flask was added4,4′-dimethylbenzhydrol (1.06 g, 5.00 mmol) and 97% sulfuric acid (44.0mL). The mixture was cooled to 15° C. by an ice/water bath and formicacid (12.0 mL) was added dropwise via an addition funnel over 0.5 h. Theresulting foaming solution was stirred at 15° C. for 2 h. Water (300 mL)was added and the pH was adjusted to 3 with potassium hydroxide pelletsand 10% KOH solution. The aqueous solution was extracted with ethylacetate (3×100 mL) and the combined organic extracts were washed withbrine (100 mL) and dried over sodium sulfate, filtered and concentratedin vacuo to give the desired product (0.281 g, 26%) as a pale yellowsolid, which was used in the subsequent step without furtherpurification: ¹H NMR (400 MHz, CD₃OD) δ 7.28-6.99 (m, 8H), 6.96 (br s,1H), 4.94 (s, 1H), 2.29 (s, 6H).

General Procedure for Scheme 8

N-[3-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE.A mixture of 2,2-diphenylacetyl chloride (0.300 mmol, 69.2 mg),N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide (0.250mmol, 75.8 mg) and triethylamine (0.500 mmol, 50.5 mg) was dissolved inTHF (2.00 mL) and the mixture was shaken on an Orbital J-KEM Shaker atroom temperature for 12 h. The reaction mixture was concentrated invacuo, and the residue was purified by preparative TLC [silica, CH₂Cl₂:ammonia (2.0 M in methanol) 100:5] to afford the desired product (83.3mg, 62% yield): ¹H NMR (400 MHz, CDCl₃) δ 7.51 (s, 1H), 7.33-7.21 (m,13H), 6.94 (m, 2H), 4.88 (s, 1H), 3.39 (t, 2H, J=5.6 Hz), 2.93 (d, 2H,J=11.3 Hz), 2.52-2.36 (m, 4H), 1.97 (t, 2H, J=11.3 Hz), 1.83-1.58 (m,6H), 1.24 (d, 6H, J=7.6 Hz); Anal. Calcd for C₃₂H₃₉N₃O₂+HCl+0.19CHCl₃:C, 69.44; H, 7.27; N, 7.55. Found: C, 69.44; H, 7.43; N, 7.43; ESMS m/e:498.4 (M+H)⁺.

General Procedure for Scheme 9

N-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-2,2-DIPHENYLPROPANAMIDE. A mixture of 2,2-diphenylpropionic acid (0.200 mmol, 45.2mg), N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide(0.200 mmol, 60.7 mg), 1-[3(dimethylamino)propyl]3-ethylcarbodiimide(EDC, 0.400 mmol, 62.0 mg) and 4-dimethylaminopyridine (5.00 mg) wasdissolved in CH₂Cl₂/DMF (1.00/0.100 mL) and the mixture was shaken on anorbital J-KEM shaker at room temperature for 12 h. The reaction mixturewas concentrated in vacuo, purified by preparative TLC [silica,CH₂Cl₂:ammonia (2.0 M in methanol) 100:5] to afford the desired product(43.8 mg, 42% yield): ¹H NMR (400 MHz, CDCl₃) δ 7.50-7.43 (br, 1H),7.43-7.39 (br, 1H), 7.39-7.18 (m, 12H), 6.89 (d, 1H, J=7.7 Hz), 6.23(br, 1H) 3.42-3.32 (m, 2H), 2.85 (d, 2H, J=10.8 Hz), 2.50 (quintet, 1H,J=7.4 Hz), 2.45-2.36 (m, 1H), 2.28 (t, 2H, J=6.4 Hz), 1.99 (s, 3H),1.96-1.82 (m, 2H), 1.78-1.60 (m, 4H), 1.60-1.47 (m, 2H), 1.23 (d, 6H,J=7.0 Hz); ESMS m/e: 512.4 [M+H]⁺.

General Procedure for Scheme 10

A library of amides was constructed in polypropylene Robbins “ReactorBlocks”, 48 well plates. PS-CDI resin (300 mg, 2.00 eq, purchased fromArgonaut Technologies) was placed in each well of the “Reactor Blocks”48 well plates. To each well was added an amine (0.200 mmol) and acarboxylic acid (0.22 mmol) in 3.00 mL of CH₂Cl₂ and DMF (10:1). TheReactor Blocks were sealed and rotated in a Robbins oven (FlexChem) atroom temperature for 12 h. The solutions were filtered in parallel intoRobbins receiving plates and the resin was washed with CH₂Cl₂ (2.0 mL)and MeOH (1.0 mL). The filtrate and washings were concentrated underreduced pressure to give the desired product, which was analyzed by ¹HNMR and ESMS.

2-(4-CHLOROPHENYL)-2-METHYL-N-(3-{4-[3-(PROPIONYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)PROPANAMIDE:Prepared according to the general procedure outlined in Scheme 10 using2-(4-chlorophenyl)-2-methylpropanoic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide: ¹H NMR (400MHz, CDCl₃) δ 7.86 (s, 1H), 7.50 (s, 1H), 7.34-7.19 (m, 6H), 6.96 (d,1H, J=7.8 Hz), 6.72-6.67 (m, 1H), 3.42 (q, 2H, J=7.1 Hz), 3.31 (q, 3H,J=5.4 Hz), 2.49-2.35 (m, 5H), 2.08-1.95 (m, 2H), 1.82-1.74 (m, 2H),1.71-1.62 (m, 3H), 1.56 (s, 6H), 1.24 (t, 3H, J=7.8 Hz); ESMS m/e: 470.3[M+H]⁺.

General Procedure for Scheme 11

(4S)-3-[(4-fluorophenyl)acetyl]4-isopropyl-1,3-oxazolidin-2-one: To asolution of (4S)-4-isopropyl-1,3-oxazolidin-2-one (2.0 g, 15.5 mmol) indry THF (20 mL) at −78° C. under argon, was added dropwise a 2.5Msolution of n-BuLi in hexanes (6.2 mL, 15.5 mmol). After stirring at−78° C. for 15 min, (4-fluorophenyl)acetyl chloride (2.55 mL, 18.6 mmol)was added. The resulting reaction mixture was stirred at −78° C. for 30min and 0° C. for 15 min, quenched with saturated NH₄Cl (5 mL) andconcentrated in vacuo. The residue was dissolved in EtOAc (100 mL) andwashed with saturated Na₂CO₃ following by brine, dried over MgSO₄,filtered and concentrated in vacuo. The crude material was purified byflash chromatography (10%-15% EtOAc/hexane) to give 2.83 g (10.7 mmol,69%) of (4S)-3[(4-fluorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one:¹H NMR (400 MHz, CDCl₃) δ 7.30-7.25 (m, 2H), 7.10 (t, 2H. J=8.5 Hz),4.46-4.41 (m, 1H), 4.36-4.15 (m, 4H), 2.40-2.28 (m, 1H), 0.88 (d, 3H,J=7.6 Hz), 0.79 (d, 3H, J=7.6 Hz); ESMS m/e: 266.2 (M+H)⁺.

(4S)-3-[(4-chlorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one: To asolution of (4S)-4-isopropyl-1,3-oxazolidin-2-one (2.0 g, 15.5 mmol) indry THF (20 mL) at −78° C. under argon, was added dropwise a 2.5Msolution of n-BuLi in hexanes (6.2 mL, 15.5 mmol). After stirring at−78° C. for 15 min, (4-chlorophenyl)acetyl chloride (2.70 mL, 21.8 mmol)was added. The resulting reaction mixture was stirred at −78° C. for 30min and 0° C. for 15 min, quenched with saturated NH₄Cl (5 mL) andconcentrated in vacuo. The residue was dissolved in EtOAc (100 mL) andwashed with saturated Na₂CO₃ following by brine, dried over MgSO₄,filtered and concentrated in vacuo. The crude material was purified byflash chromatography (10%-15% EtOAc/hexane) to give 2.33 g (8.29 mmol,53%) of(4S)-3-[(4-chlorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one: ¹H NMR(400 MHz, CDCl₃) δ 7.31-7.22 (m, 4H), 4.45-4.41 (m, 1H), 4.35-4.16 (m,4H), 2.39-2.29 (m, 1H), 0.89 d, 3H, J=7.2 Hz), 0.80 (d, 3H, J=7.2 Hz);ESMS m/e: 282.2 (M+H)⁺.

(4R)-3-[(4-fluorophenyl)acetyl]-isopropyl-1,3-oxazolidin-2-one: To asolution of (4R)-4-isopropyl-1,3-oxazolidin-2-one (5.2 g, 40.3 mmol) indry THF (100 mL) at −78° C. under argon, was added dropwise a 2.5Msolution of n-BuLi in hexanes (17.0 mL, 42.5 mmol). After stirring at−78° C. for 15 min, (4-fluorophenyl)acetyl chloride (6.34 mL, 46.4 mmol)was added. The resulting reaction mixture was stirred at −78° C. for 30min and 0° C. for 15 min, quenched with saturated NH₄Cl (15 mL) andconcentrated in vacuo. The residue was dissolved in EtOAc (200 mL) andwashed with saturated Na₂CO₃ following by brine, dried over MgSO₄,filtered and concentrated in vacuo. The crude material was purified byflash chromatography (10%-15% EtOAc/hexane) to give 8.35 g (31.5 mmol,78%) of(4R)-3-[(4-fluorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one: ¹H NMR(400 MHz, CDCl₃) δ 7.30-7.25 (m, 2H), 7.10 (t, 2H, J=8.5 Hz), 4.46-4.41(m, 1H), 4.36-4.15 (m, 4H), 2.40-2.28 (m, 1H), 0.88 (d, 3H, J=7.6 Hz),0.79 (d, 3H, J=7.6 Hz); ESMS m/e: 266.1 (M+H)⁺.

(4R)-3-[(4-chlorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one: To asolution of (4R)-4-isopropyl-1,3-oxazolidin-2-one (5.3 g, 41.1 mmol) indry THF (100 mL) at −78° C. under argon, was added dropwise a 2.5Msolution of n-BuLi in hexanes (17.0 mL, 42.5 mmol). After stirring at−78° C. for 15 min, (4-chlorophenyl)acetyl chloride (2.70 mL, 21.8 mmol)was added. The resulting reaction mixture was stirred at −78° C. for 30min and 0° C. for 15 min, quenched with saturated NH₄Cl (15 mL) andconcentrated in vacuo. The residue was dissolved in EtOAc (200 mL) andwashed with saturated Na₂CO₃ following by brine, dried over MgSO₄,filtered and concentrated in vacuo. The crude material was purified byflash chromatography (10%-15% EtOAc/hexane) to give 6.48 g (23.1 mmol,56%) of(4R)-3-[(4-chlorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one: ¹H NMR(400 MHz, CDCl₃) δ 7.31-7.22 (m, 4H), 4.45-4.41 (m, 1H), 4.35-4.16 (m,4H), 2.39-2.29 (m, 1H), 0.89 d, 3H, J=7.2 Hz), 0.80 (d, 3H, J=7.2 Hz);ESMS m/e: 282.1 (M+H)⁺.

(4S)-3-[(2S)-2-(4-fluorophenyl)propanoyl]-4-isopropyl-1,3-oxazolidin-2-one:To a solution of(4S)-3-[(4-fluorophenyl)acetyl]4-isopropyl-1,3-oxazolidin-2-one (2.81 g,10.6 mmol) in dry THF (40 mL) at −78° C. under argon, was added dropwise1.0M solution of NaHMDS in THF (11.7 mL, 11.7 mmol) over a period of 10min. After stirring at −78° C. for 1 h, MeI (3.30 mL, 53.0 mmol) wasadded. The resulting reaction mixture was stirred at −78° C. for 1 h and−40° C. for 2 h, quenched with HOAc (32 mmol) in ether (20 mL), filteredover celite. The filtrate was concentrated in vacuo and the residue wasdissolved in CH₂Cl₂ (100 mL) and washed with H₂O following by brine,dried over MgSO₄, filtered and concentrated in vacuo. The crude materialwas purified by flash chromatography (5%-10% EtOAc in hexane) to give2.40 g (8.60 mmol, 81%) of(4S)-3-[(2S)-2-(4-fluorophenyl)propanoyl]isopropyl-1,3-oxazolidin-2-one:¹H NMR (400 MHz, CDCl₃) δ 7.34-7.31 (m, 2H), 7.02-6.96 (m, 2H), 5.13 (q,1H, J=7.7 Hz), 4.38-4.33 (m, 1H), 4.18-4.13 (m, 2H), 2.48-2.37 (m, 1H),1.49 (d, 3H, J=7.3 Hz), 0.91 (apparent t, 6H, J=6.9 Hz); ESMS m/e: 280.2(M+H)⁺.

(4S)-3-[(2S)-2-(4-chlorophenyl)propanoyl]-4-isopropyl-1,3-oxazolidin-2-one:To a solution of(4S)-3-[(4-chlorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one (1.07g, 3.81 mmol) in dry THF (30 mL) at −78° C. under argon, was addeddropwise 1.0M solution of NaHMDS in THF (4.20 mL, 4.20 mmol) over aperiod of 10 min. After stirring at −78° C. for 1 h, MeI (1.19 mL, 19.1mmol) was added. The resulting reaction mixture was stirred at −78° C.for 1 h and −40° C. for 2 h, quenched with HOAc (11.4 mmol) in ether (20mL), filtered over celite. The filtrate was concentrated in vacuo andthe residue was dissolved in CH₂Cl₂ (50 mL) and washed with H₂Ofollowing by brine, dried over MgSO₄, filtered and concentrated invacuo. The crude material was purified by flash chromatography (5%-10%EtOAc in hexane) to give 0.68 g (2.30 mmol, 60%) of(4S)-3-[(2S)-2-(4-chlorophenyl)propanoyl]-isopropyl-1,3-oxazolidin-2-one:¹H NMR (400 MHz, CDCl₃) δ 7.30-7.23 (m, 4H), 5.11 (q, 1H, J=7.9 Hz),4.35 (quintet, 1H, J=3.7 Hz), 4.16-4.09 (m, 2H), 2.46-2.36 (m, 1H), 1.49(d, 3H, J=7.3 Hz), 0.91 (apparent t, 6H, J=6.9 Hz); ESMS m/e: 296.2(M+H)⁺.

(4R)-3-[(2R)-2-(4-fluorophenyl)propanoyl]-isopropyl-1,3-oxazolidin-2-one:To a solution of(4R)-3-[(4-fluorophenyl)acetyl]-isopropyl-1,3-oxazolidin-2-one (4.24 g,16.0 mmol) in dry THF (80 mL) at −78° C. under argon, was added dropwise1.0M solution of NaHMDS in THF (17.6 mL, 17.6 mmol) over a period of 10min. After stirring at −78° C. for 1 h, MeI (5.0 mL, 80.0 mmol) wasadded. The resulting reaction mixture was stirred at −78° C. for 1 h and−40° C. for 2 h, quenched with HOAc (48 mmol) in ether (20 mL), filteredover celite. The filtrate was concentrated in vacuo and the residue wasdissolved in CH₂Cl₂ (200 mL) and washed with H₂O following by brine,dried over MgSO₄, filtered and concentrated in vacuo. The crude materialwas purified by flash chromatography (5%-10% EtOAc in hexane) to give2.59 g (9.28 mmol, 58%) of(4R)-3-[(2R)-2-(4-fluorophenyl)propanoyl]-4-isopropyl-1,3-oxazolidin-2-one:¹H NMR (400 MHz, CDCl₃) δ 7.34-7.31 (m, 2H), 7.02-4.96 (m, 2H), 5.13 (q,1H, J=7.7 Hz), 4.38-4.33 (m, 1H), 4.18-4.13 (m, 2H), 2.48-2.37 (m, 1H),1.49 (d, 3H, J=7.3 Hz), 0.91 (apparent t, 6H, J=6.9 Hz); ESMS m/e: 280.2(M+H)⁺.

(4R)-3-[(2R)-2-(4-chlorophenyl)propanoyl]-4-isopropyl-1,3-oxazolidin-2-one:To a solution of(4R)-3-[(4-chlorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one (2.80g, 9.96 mmol) in dry THF (80 mL) at −78° C. under argon, was addeddropwise 1.0M solution of NaHMDS in THF (11.0 mL, 11.0 mmol) over aperiod of 10 min. After stirring at −78° C. for 1 h, MeI (1.9 mL, 30.0mmol) was added. The resulting reaction mixture was stirred at −78° C.for 1 h and −40° C. for 2 h, quenched with HOAc (30.0 mmol) in ether (20mL), filtered over celite. The filtrate was concentrated in vacuo andthe residue was dissolved in CH₂Cl₂ (100 mL) and washed with H₂Ofollowing by brine, dried over MgSO₄, filtered and concentrated invacuo. The crude material was purified by flash chromatography (5%-10%EtOAc in hexane) to give 1.58 g (5.35 mmol, 54%) of(4R)-3-[(2R)-2-(4-chlorophenyl)propanoyl]-4-isopropyl-1,3-oxazolidin-2-one:¹H NMR (400 MHz, CDCl₃) δ 7.30-7.23 (m, 4H), 5.11 (q, 1H, J=7.9 Hz),4.35 (quintet, 1H, J=3.7 Hz), 4.16-4.09 (m, 2H), 2.46-2.36 (m, 1H), 1.49(d, 3H, J=7.3 Hz), 0.91 (apparent t, 6H, J=6.9 Hz); ESMS m/e: 296.1(M+H)⁺.

(2S)-2-(4-fluorophenyl)propanoic acid: To a solution of(4S)-3-[(2S)-2-(4-fluorophenyl)propanoyl]-4-isopropyl-1,3-oxazolidin-2-one (2.40 g, 8.60 mmol) in 160mL THF/H₂O (3:1) at 0° C., was added 30% H₂O₂ (7.8 mL, 68.8 mmol)followed by LiOH (722 mg, 17.2 mmol). The resulting mixture was stirredat 0° C. for 2 h and the excess peroxide was quenched at 0° C. with 1.5N aqueous Na₂SO₃ (51 mL). After buffering to pH 9-10 with aqueous NaHCO₃and evaporation of the THF, the oxazolidone chiral auxiliary wasrecovered by EtOAc extraction (50 mL×3). The aqueous layer was acidifiedwith 3N HCl and extracted with EtOAc. The organic layer was washed withbrine, dried over MgSO₄, filtered and concentrated in vacuo to give 0.92g (5.47 mmol, 64%) of (2S)-2-(4-fluorophenyl)propanoic acid;[α]_(D)=+70° (C=1, MeOH): ¹H NMR (400 MHz, CDCl₃) δ 12.2-11.4 (br, 1H),7.31-7.24 (m, 2H), 7.04-6.97 (m, 2H), 3.72 (q, 1H, J=7.3 Hz), 1.49 (d,3H, J=7.3 Hz); ESMS m/e: 167.2 (M−H)⁺.

(2S)-2-(4-chlorophenyl)propanoic acid: To a solution of(4S)-3-[(2S)-2-(4-chlorophenyl)propanoyl]-4-isopropyl-1,3-oxazolidin-2-one (678 mg, 2.30 mmol) in 45 mLTHF/H₂O (3:1) at 0° C., was added 30% H₂O₂ (2.1 mL, 18.4 mmol) followedby LiOH (193 mg, 4.6 mmol). The resulting mixture was stirred at 0° C.for 2 h and the excess peroxide was quenched at 0° C. with 1.5 N aqueousNa₂SO₃ (15 mL). After buffering to pH 9-10 with aqueous NaHCO₃ andevaporation of the THF, the oxazolidone chiral auxiliary was recoveredby EtOAc extraction (50 mL×3). The aqueous layer was acidified with 3NHCl and extracted with EtOAc. The organic layer was washed with brine,dried over MgSO₄, filtered and concentrated in vacuo to give 0.36 g(1.96 mmol, 85%) of (2S)-2-(4-chlorophenyl)propanoic acid; [α]_(D)=+67°(C=1, MeOH): ¹H NMR (400 MHz, CDCl₃) δ 12.2-10.8 (br, 1H), 7.32-7.23 (m,4H), 3.72 (q, 1H, J=7.3 Hz), 1.50 (d, 3H, J=7.3 Hz); ESMS m/e: 183.2(M−H)⁺.

(2R)-2-(4-fluorophenyl)propanoic acid: To a solution of(4R)-3-[(2R)-2-(4-fluorophenyl)propanoyl]-isopropyl-1,3-oxazolidin-2-one(2.59 g, 9.28 mmol) in 160 mL THF/H₂O (3:1) at 0° C., was added 30% H₂O₂(8.4 mL, 74.2 mmol) followed by LiOH (780 mg, 18.6 mmol). The resultingmixture was stirred at 0° C. for 2 h and the excess peroxide wasquenched at 0° C. with 1.5 N aqueous Na₂SO₃ (54 mL). After buffering topH 9-10 with aqueous NaHCO₃ and evaporation of the THF, the oxazolidonechiral auxiliary was recovered by EtOAc extraction (50 mL×3). Theaqueous layer was acidified with 3N HCl and extracted with EtOAc. Theorganic layer was washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo to give 1.43 g (8.51 mmol, 92%) of(2R)-2-(4-fluorophenyl)propanoic acid; [α]_(D)=−61.5° (C=1.04, MeOH): ¹HNMR (400 MHz, CDCl₃) δ 12.2-11.4 (br, 1H), 7.31-7.24 (m, 2H), 7.04-6.97(m, 2H), 3.72 (q, 1H, J=7.3 Hz), 1.49 (d, 3H, J=7.3 Hz); ESMS m/e: 167.2(M−H)⁺.

(2R)-2-(4-chlorophenyl)propanoic acid: To a solution of(4R)-3-[(2R)-2-(4-chlorophenyl)propanoyl]-4-isopropyl-1,3-oxazolidin-2-one (1.58 g, 5.35 mmol) in 45 mLTHF/H₂O (3:1) at 0° C., was added 30% H₂O₂ (4.9 mL, 42.8 mmol) followedby LiOH (449 mg, 10.7 mmol). The resulting mixture was stirred at 0° C.for 2 h and the excess peroxide was quenched at 0° C. with 1.5 N aqueousNa₂SO₃ (31 mL). After buffering to pH 9-10 with aqueous NaHCO₃ andevaporation of the THF, the oxazolidone chiral auxiliary was recoveredby EtOAc extraction (50 mL×3). The aqueous layer was acidified with 3NHCl and extracted with EtOAc. The organic layer was washed with brine,dried over MgSO₄, filtered and concentrated in vacuo to give 0.97 g(5.27 mmol, 98%) of (2R)-2-(4-chlorophenyl)propanoic acid;[α]_(D)=−64.8° (C=1.05, MeOH): ¹H NMR (400 MHz, CDCl₃) δ 12.2-10.8 (br,1H), 7.32-7.23 (m, 4H), 3.72 (q, 1H, J=7.3 Hz), 1.50 (d, 3H. J=7.3 Hz);ESMS m/e: 183.2 (M−H)⁺.

General Procedure for Scheme 12

For intermediate RCOOH are available from commercial sources oralternatively may be prepared from a variety of intermediates known tothose skilled in the art. For example, α-substituted aryl acetic acidcan be prepared by hydrolysis of corresponding α-substitutedarylacetonitriles or α-substituted aryl acetic esters (Rieu, et al.,1986. Tetrahedron 42(15) 4095-4131 and references cited therein).

Enantiomerically pure-substituted aryl acetic acid can be prepared byasymmetric syntheses or enzymatic kinetic resolution (Evans, inAsymmetric Synthesis, ed. Morrison 1984. Vol 3, Academic Press, NewYork; Li, et al., 2001. Tetrahedron: Asymmetry 12, 3305-3312 andreferences cited therein).

Enantiomerically pure α-hydroxy carboxylic acid can be prepared byasymmetric syntheses or kinetic resolution (Chang, et al., 1999. Org.Lett. 13 2061-2063; Deng, et al., 2002. J. Am. Chem. Soc. 124(12)2870-2871; Bull, et al., 2003. Tetrahedron: Asymmetry 14, 1407-1446 andreferences cited therein).

The enantiomeric purity is determined by NMR or HPLC (Parker, 1991.Chem. Rev. 91 1441-1457 and references cited therein). Many othermethods to produce acid intermediates are known in the literature andmay be utilized by those skilled in the art for their preparation.

General Procedure for Scheme 13

Step 1

A 25 mL RB-flask was charged with ethyl iodide (1.00 mmol, 156 mg),N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide (1.00mmol, 303 mg), sodium tert-butoxide (2.00 mmol, 192 mg) and THF (5.00mL). The mixture was shaken on an J-KEM orbital shaker at roomtemperature for 12 h. The reaction mixture was concentrated in vacuo andpurified by preparative TLC [silica, CH₂Cl₂:ammonia (2.0 M in methanol)100:5] to afford the desired product (28.5 mg, 9% yield): ¹H NMR (400MHz, CDCl₃) δ 7.47 (s, 1H), 7.40-7.30 (m, 1H), 7.23-7.19 (m, 1H),7.01-6.95 (m, 2H), 3.70 (q, 2H, J=6.0 Hz), 3.10-3.02 (m, 2H), 2.81-2.75(m, 2H), 2.50-2.41 (m, 4H), 2.09-2.01 (m, 2H), 1.83-1.67 (m, 6H), 1.24(d, 7H, J=6.0 Hz), 1.08 (t, 3H, J=6.0 Hz).

Step 2: See Scheme 9.

General Procedure for Scheme 14

N-(3-BROMOPROPYL)-2,2-DIPHENYLACETAMIDE. To a stirred mixture of3-bromopropylamine hydrobromide (2.91 g, 13.3 mmol) in 10 mL of CH₂Cl₂was added 2.8 mL of triethylamine (20.0 mmol). The reaction mixture wasstirred at room temperature for 10 minutes, followed by addition ofdiphenyl acetyl chloride (2.56 g, 11.1 mmol) and triethylamine (2.8 mL,20 mmol) in CH₂Cl₂ (10 mL). The reaction mixture was stirred for 40minutes at room temperature and then diluted with 200 mL of CH₂Cl₂. Thesolution was washed with aqueous 0.5 N HCl (100 mL×3), water (50 mL),NaHCO₃ (sat, 100 mL) and NaCl (sat), dried over MgSO₄. Removal ofsolvent gave the crude product as a light yellow solid that was used inthe next step without further purification (3.33 g, 91%): ¹H NMR (400MHz, CDCl₃) δ 7.56-7.45 (m, 10H), 5.88-5.69 (br, 1H), 4.92 (s, 1H),3.47-3.39 (m, 2H), 3.35 (t, 2H, J=6.4 Hz), 2.16-1.98 (m, 2H).

N-[4-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:A mixture of 2-methyl-N-[4-(4-piperidinyl)phenyl]propanamide (50.0 mg,2.0 mmol), N-(3-bromopropyl)-2,2-diphenylacetamide (64.2 mg, 0.2 mmol),K₂CO₃ (55.0 mg, 4.0 mmol), and NaI (45.0 mg, 0.3 mmol) in 2 mL of DMFwas stirred at room temperature for 10 minutes followed by heating to80-90° C. for 12 h. The reaction mixture was cooled to room temperatureand purified by preparative TLC (silica gel, EtOAc/NH₃ (2 M in MeOH);95:5) to affordN-[4-(1-{3-[(diphenylacetyl)amino]propyl}-4-piperidinyl)phenyl]-2-methylpropanamideas a colorless oil (15.7 mg, 32%): ESMS m/e: 498.3 (M+H)⁺.

General Procedure for Scheme 15

N-{3-[4-(3-AMINOPHENYL)-1-PIPERIDINYL]}-2,2-DIPHENYLACETAMIDE: A 25 mLRB-flask, equipped with a balloon of hydrogen, was charged with benzyl3-(1-{3-[(diphenylacetyl)amino]propyl}-4-piperidinyl] phenylcarbamate(78.7 mg, 0.140 mmol), Pd/C (10 mol %, 14.8 mg) and ethanol (2.00 mL) atroom temperature. The mixture was stirred at room temperature for 12 hand filtered through a plug of Celite. The Celite was washed withmethylene chloride (3×5 mL) and the filtrate was concentrated in vacuo.The residue was purified by preparative TLC [silica, CH₂Cl₂: ammonia(2.0 M in methanol) 100:5] to affordN-{3-[4-(3-aminophenyl)-1-piperidinyl]}-2,2-diphenylacetamide: ¹H NMR(400 MHz, CDCl₃) δ 7.34-7.08 (m, 15H), 4.59 (s, 1H), 3.38-3.31 (m, 1H),3.24-3.15 (m, 2H), 2.71-2.64 (m, 1H), 2.49-2.28 (m, 3H), 2.08-1.89 (m,3H), 1.84-1.49 (m, 6H); ESMS m/e: 428.3 (M+H)⁺.

General Procedure for Scheme 16

1-bromo-2,4-difluoro-5-nitrobenzene: To a suspension of1-bromo-2,4-difluorobenzene (6.0 mL, 53.0 mmol) in concd H₂SO₄ (38.5 mL)at 0° C. was added dropwise concd HNO₃ (34.0 mL) maintaining an internaltemperature below 20° C. The resulting mixture was stirred for 30 min at0° C., then poured slowly into ice water with vigorous stirring. Theaqueous phase was separated and extracted with EtOAc. The combinedorganic extrats were washed with 5% aqueous KOH and brine, dried overMgSO₄ and concentrated to give 12.2 g (51.5 mmol, 97%) of1-bromo-2,4-difluoro-5-nitrobenzene: ¹H NMR (400 MHz, CDCl₃) δ 8.39 (t,1H, J=7.4 Hz), 7.13 (dd, 1H, J=7.7, 10.3 Hz).

2-bromo-1,3,5-trifluoro-4-nitrobenzene: ¹H NMR (400 MHz, CDCl₃) δ7.05-6.98 (m, 1H); ESMS m/e: 256.2 (M+H)⁺.

5-bromo-2,4-difluoroaniline: To a solution of1-bromo-2,4-difluoro-5-nitrobenzene (5.04 g, 21.3 mmol) in EtOH (100mL), THF (50 mL), NH₄Cl_((sat)) (25 mL) and H₂O (25 mL) was added ironpowder (5.0 g, 89.5 mmol). The mixture was refluxed for 2 h and filteredthrough celite. The filter pad was washed with EtOAc (3×50 mL). Thefiltrate was concentrated and the residue was partitioned between EtOAcand brine. The organic layer was dried over MgSO₄ and concentrated.Purification by flash chromatography (5-10% EtOAc/Hexane) provided 2.6 g(59%) of 5-bromo-2,4-difluoroaniline: ESMS m/e: 208.2 (M+H)⁺.

3-bromo-2,4,6-trifluoroaniline: ¹H NMR (400 MHz, CDCl₃) δ 6.85-6.76 (m,1H), 3.78-3.51 (br, 2H).

N-(5-bromo-2,4-difluorophenyl)-2-methylpropanamide

Into a solution of 2.6 g (12.6 mmol) of 5-bromo-2,4-difluoroaniline and2.1 mL (15.1 mmol) of triethylamine in 50 mL THF at 0° C. was slowlyadded 1.6 mL (15.1 mmol) of isobutyryl chloride. The reaction mixturewas stirred at room temperature for 2 hours and concentrated in vacuo.The residue was dissolved in EtOAc and washed with H₂O, saturatedaqueous Na₂CO₃ and brine. The organic layer was dried over MgSO₄ andconcentrated in vacuo to give 3.3 g (11.8 mmol, 94%) ofN-(5-bromo-2,4-difluorophenyl)-2-methylpropanamide: ESMS m/e: 278.1(M+H)⁺.

N-(3-bromo-2,4,6-trifluorophenyl)-2-methylpropanamide: ESMS m/e: 296.3(M+H)⁺.

tert-butyl4-[2,4-difluoro-5-(isobutyrylamino)phenyl]3,6-dihydro-1(2H)-pyridinecarboxylate: To a 250-mL RB flask containing tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate(3.31 g, 10.7 mmol), K₂CO₃ (4.44 g, 32.1 mmol) and PdCl₂dppf (870 mg,1.07 mmol) was added a solution ofN-(5-bromo-2,4-difluorophenyl)-2-methylpropanamide (3.28 g, 11.8 mmol)in DMF (100 mL) at room temperature under argon. The mixture was heatedto 80° C. under argon overnight, cooled to room temperature, filteredthrough celite and the celite was washed with EtOAc (3×20 mL). Thefiltrates were washed with H₂O (20 mL), brine (20 mL), dried over MgSO₄,filtered and concentrated in vacuo. The crude material was purified byflash chromatography (10%-20% EtOAc/hexane) to give 2.4 g (6.31 mmol,59%) of tert-butyl4-[2,4-difluoro-5-(isobutyrylamino)phenyl]-3,6-dihydro-1(2H)-pyridinecarboxylate: ESMS m/e: 379.3 (M−H)⁺.

tert-butyl 4-[2,4,6-trifluoro-3-(isobutyrylamino)phenyl]-3,6-dihydro-1(2H)pyridinecarboxylate: ESMS m/e: 397.6 (M−H)⁺.

tert-butyl4-[2,4-difluoro-5-(isobutyrylamino)phenyl]-piperidinecarboxylate: Asolution of tert-butyl4-[2,4-difluoro-5-(isobutyrylamino)phenyl]-3,6-dihydro-1(2H)-pyridinecarboxylate(2.40 g, 6.31 mmol) and 10% Pd/C (500 mg) in EtOAc (40.0 mL) and MeOH(10.0 mL) was hydrogenated (200 psi) at room temperature overnight. Thereaction mixture was filtered through celite and washed with ethanol(3×10 mL). The combined extracts were concentrated in vacuo to afford2.04 g (5.34 mmol, 85%) of tert-butyl4-[2,4-difluoro-5-(isobutyrylamino)phenyl]-1-piperidinecarboxylate: ESMSm/e: 383.2 (M+H)⁺.

N-[2,4-difluoro-5-(4-piperidinyl)phenyl]-2-methylpropanamide: Into asolution of tert-butyl4-[2,4-difluoro-5-(isobutyrylamino)phenyl]-1-piperidinecarboxylate (6.54g, 17.1 mmol) in 1,4-dioxane (40.0 mL) was added 4M HCl in 1,4-dioxane(160 mL) at room temperature. The reaction mixture was stirred for 1 hand concentrated in vacuo. The residue was dissolved in 100 mL of H₂Oand was basified with 10% KOH solution (50 mL). The aqueous layer wasextracted with CHCl₃/i-PrOH (3:1, 3×150 mL). The combined organicextracts were washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo to give 4.72 g (16.7 mmol, 98%) ofN-[2,4-difluoro-5-(4-piperidinyl)phenyl]-2-methylpropanamide: ESMS m/e:283.3 (M+H)⁺.

2-methyl-N-[2,4,6-trifluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)phenyl]propanamide:ESMS m/e: 299.5 (M+H)⁺.2-methyl-N-[2,4,6-trifluoro-3-(4-piperidinyl)phenyl] propanamide: ESMSm/e: 301.3 (M+H)⁺.

General Procedure for Scheme 17

benzyl 5-bromo-3-pyridinylcarbamate: To a suspension of 5-bromonicotinicacid (20.0 g, 99.0 mmol) in toluene (200 mL) was addeddiphenylphosphoryl azide (25.6 mL, 118.8 mmol) and Et₃N (16.6 mL, 118.8mmol). After stirring at room temperature for 30 min, benzyl alcohol(15.4 mL, 148.5 mmol) was added. The mixture was stirred at roomtemperature for 1 h then refluxed overnight. The cold reaction mixturewas washed with H₂O, NaHCO₃ and brine, dried over MgSO₄ andconcentrated. Purification by flash chromatography (1-50% EtOAc/Hexane)provided 22.2 g (72.5 mmol, 73%) of benzyl 5-bromo-3-pyridinylcarbamate:ESMS m/e: 307.0 (M+H)⁺.

tert-butyl4-{5-[(phenylmethoxy)carbonylamino]-3-pyridyl}-1,2,5,6-tetrahydropyridinecarboxylate

ESMS m/e: 410.2 (M+H)⁺. tert-butyl4-(5-amino-3-pyridinyl)-1-piperidinecarboxylate: ESMS m/e: 278.3 (M+H)⁺.tert-butyl 4-[5-(isobutyrylamino)-3-pyridinyl]-1-piperidine carboxylate:ESMS m/e: 348.3 (M+H)⁺.2-methyl-N-[5-(4-piperidinyl)-3-pyridinyl]propanamide: ESMS m/e: 248.3(M+H)⁺.

General Procedure for Scheme 18

Bis(4-fluorophenyl)(hydroxy)acetic acid

To a solution prepared from 10.2 g of KOH and 50 ml of 50% EtOH wasadded 1,2-bis(4-fluorophenyl)-1,2-ethanedione (10.0 g, 40.6 mmol) andthe mixture was heated at reflux temperature overnight. After cooling toroom temperature, the mixture was washed with ether (100 mL×2). Theaqueous layer was cooled to 0° C., acidified with 12 N HCl (20 mL) andextracted with CH₂Cl₂ (150 mL×2). The combined organic layers werewashed with brine, dried over MgSO₄, filtered and concentrated in vacuoto give 9.15 g (34.7 mmol, 85%) of bis(4-fluorophenyl)(hydroxy)aceticacid: ESMS m/e: 263.2 (M−H)⁺.

Hydroxy[bis(4-methylphenyl)]acetic acid

To a solution prepared from 10.6 g of KOH and 50 ml of 50% ETOH wasadded 1,2-bis(4-methylphenyl)-1,2-ethanedione (10.0 g, 42.0 mmol) andthe mixture was heated at reflux temperature overnight. After cooled toroom temperature, the mixture was washed with ether (100 mL×2). Theaqueous layer was cooled to 0° C., acidified with 12 N HCl (20 mL) andextracted with CH₂Cl₂ (150 mL×2). The combined organic layers werewashed with brine, dried over MgSO₄, filtered and concentrated in vacuoto give 9.56 g (37.3 mmol, 89%) of hydroxy[bis(4-methylphenyl)]aceticacid: ESMS m/e: 255.3 (M−H)⁺.

EXAMPLE 1

N-{3-[1-(3-{[BIS(4-FLUOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]PHENYL}-2-METHYLPROPANAMIDE: Example 1 was prepared frombis(4-fluorophenyl) acetic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 7.63 (s, 1H), 7.39-7.31 (m, 3H), 7.29-7.21 (m, 5H), 7.02-6.96(m, 4H), 4.80 (s, 1H), 3.40 (q, 2H, J=4.5 Hz), 2.94 (d, 2H, J=10.2 Hz),2.51-2.38 (m, 4H), 1.97(dt, 2H, J=1.8, 10.4 Hz), 1.81 (m, 2H), 1.68(quintet, 2H, J=6.8 Hz,), 1.59 (m, 3H), 1.23 (d, 6H, J=6.9 Hz); ESMSm/e: 534.3 (M+H)⁺; Anal. Calc. For (HCl salt)C₃₂H₃₇F₂N₃O₂.HCl.0.20CHCl₃: C, 65.11; H, 6.48; N, 7.07. Found: C, 65.30;H, 6.50; N, 6.96.

EXAMPLE 2

N-{3-[1-(3-{[BIS(4-CHLOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]PHENYL}-2-METHYLPROPANAMIDE: Example 2 was prepared frombis(4-chlorophenyl) acetic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl] phenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 7.64 (s, 1H), 7.34-7.13 (m, 12H), 4.75 (s, 1H), 3.41 (q, 2H,J=4.5 Hz), 2.94 (d, 2H, J=10.2 Hz), 2.51-2.40 (m, 4H), 1.97 (m, 2H),1.82 (m, 2H), 1.68 (quintet, 2H, J=6.8 Hz), 1.59 (m, 3H), 1.25 (d, 6H,J=6.8 Hz); ESMS m/e: 566.2 (M+H)⁺.

EXAMPLE 3

N-(3-{4-[3-(acetylamino)phenyl]-piperidinyl}propyl)-2,2-diphenylacetamide:Example 3 was prepared from diphenylacetyl chloride andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to theprocedures described in Scheme 8: ¹H NMR (400 MHz, CDCl₃) δ 7.70 (s,1H), 7.40 (s, 1H), 7.32-7.20 (m, 12H), 6.96 (t, 1H, J=4.8 Hz), 6.91 (d,1H, J=7.6 Hz), 4.87 (s, 1H), 3.39 (dd, 2H, J=6.0, 12.4 Hz), 2.90 (d, 2H,J=11.6 Hz), 2.43 (m, 1H), 2.36 (t, 2H, J=6.4 Hz), 2.11 (s, 3H), 1.94 (m,2H), 1.76 (d, 2H, J=12.4 Hz), 1.68 (t, 2H, J=6.8 Hz), 1.60 (dd, 2H,J=1.2, 8.4 Hz); ESMS m/e: 470.3 (M+H)⁺.

EXAMPLE 4

N-[3-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}A PIPERIDINYL)-4-METHYLPHENYL]-2-METHYLPROPANAMIDE: Example 4 was prepared from diphenyl acetylchloride and N-{3-[1-(3-aminopropyl)-4-piperidinyl]methylphenyl}2-methylpropanamide according to the procedures described inScheme 8: ¹H NMR (400 MHz, CDCl₃) δ 7.39-7.23 (m, 12H), 7.14 (br, 1H),7.08 (d, 1H, J=8.4 Hz), 6.90 (br, 1H), 4.91 (s, 1H), 3.41 (dd, 2H,J=6.4, 12.4 Hz), 2.95 (d, 2H, J=12.4 Hz), 2.66 (m, 1H), 2.47 (m, 1H),2.40 (t, 2H, J=6.4 Hz), 2.28 (s, 3H), 2.03-1.97 (m, 2H), 1.74-1.62 (m,6H), 1.22 (d, 6H, J=7.2 Hz); ESMS m/e: 512.3 (M+H)⁺.

EXAMPLE 5

N-[3-(1-{3-[(2,2-DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL]BUTANAMIDE: Example 5 was prepared from diphenylacetyl chloride andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to theprocedures described in Scheme 8: ¹H NMR (400 MHz, CDCl₃) δ 7.49 (s,1H), 7.35-7.23 (m, 12H), 7.20 (s, 1H), 6.95 (d, 2H, J=7.6 Hz), 4.90 (s,1H), 3.41 (dd, 2H, J=5.6, 11.6 Hz), 2.94 (d, 2H, J=11.6 Hz), 2.48 (m,1H), 2.40 (t, 2H, J=6.4 Hz), 2.34 (t, 2H, J=7.2 Hz), 1.98 (t, 2H, J=11.2Hz), 1.82-1.60 (m, 8H), 1.02 (t, 3H, J=7.2 Hz); ESMS m/e: 498.3 (M+H)⁺.

EXAMPLE 6

N-[6-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)-2-PYRIDINYL]-2-METHYLPROPANAMIDE:Example 6 was prepared from diphenylacetyl chloride andN-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamideaccording to the procedures described in Scheme 8: ¹H NMR (400 MHz,CDCl₃) δ 8.07 (d, 1H, J=8.0 Hz), 7.71-7.63 (m, 3H), 7.42-7.23 (m, 10H),6.89 (d, 1H, J=7.6 Hz), 4.96 (s, 1H), 3.41 (dd, 2H, J=5.6, 7.6 Hz), 3.00(d, 2H, J=11.6 Hz), 2.60 (m, 1H), 2.47 (t, 2H, J=6.4 Hz), 2.45 (m, 1H),2.06-2.01 (m, 2H), 1.89-1.64 (m, 6H), 1.13 (d, 6H, J=6.8 Hz); ESMS m/e:499.3 (M+H)⁺.

EXAMPLE 7

2-(4-CHLOROPHENYL)-2-METHYL-N-(3-{4-[3-(PROPIONYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)PROPANAMIDE:Example 7 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acidand N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide accordingto the procedures described in Scheme 10: ¹H NMR (400 MHz, CDCl₃) δ 7.86(s, 1H), 7.50 (s, 1H), 7.34-7.19 (m, 6H), 6.96 (d, 1H, J=7.8 Hz),6.72-6.67 (m, 1H), 3.42 (q, 2H, J=7.1 Hz), 3.31 (q, 3H, J=5.4 Hz),2.49-2.35 (m, 5H), 2.08-1.95 (m, 2H), 1.82-1.74 (m, 2H), 1.71-1.62 (m,3H), 1.56 (s, 6H), 1.24 (t, 3H, J=7.8 Hz); ESMS m/e: 470.3 (M+H)⁺.

EXAMPLE 8

2-(4-CHLOROPHENYL)-N-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-2-METHYLPROPANAMIDE: Example 8 was prepared from2-(4-chlorophenyl)-2-methylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to theprocedures described in Scheme 9: ¹H NMR (400 MHz, CDCl₃) δ 7.53 (s,1H), 7.32-7.24 (m, 7H), 6.91 (d, 1H, J=7.2 Hz), 6.67 (m, 1H), 3.31 (q,2H, J=5.5 Hz), 2.92-2.85 (m, 2H), 2.53 (septet, 1H, J=6.7 Hz), 2.43 (tt,1H, J=11.6, 3.0 Hz), 2.33 (t, 2H, J=6.7 Hz), 1.91 (dt, 2H, J=11.7, 1.8Hz), 1.78-1.72 (m, 2H), 1.65-1.59 (m, 2H), 1.56 (s, 6H), 1.52-1.45 (m,2H), 1.25 (d, 6H, J=6.7 Hz); ESMS m/e: 484.3 (M+H)⁺; Anal. Calc. for(HCl salt) C₂₈H₃₈ClN₃O₂.HCl.0.30CHCl₃: C, 61.10; H, 7.12; N, 7.55.Found: C, 60.90; H, 7.20; N, 7.64.

EXAMPLE 9

N-{3-[1-(3-{[BROMO(PHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]PHENYL}-2-METHYLPROPANAMIDE: Example 9 was prepared from bromo(phenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described inScheme 9: ESMS m/e: 500.0 (M+H)⁺.

EXAMPLE 10

N-[3-(1-{3-[(2-BROMO-2-PHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL]PROPANAMIDE: Example 10 was prepared from bromo(phenyl)aceticacid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamideaccording to the procedures described in Scheme 10: ESMS m/e: 486.1(M+H)⁺.

EXAMPLE 11

N-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-2,2-DIPHENYLHEPTANAMIDE:Example 11 was prepared from 2,2-diphenyl heptanoic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 7.65 (s, 1H), 7.45 (s, 1H), 7.40 (m, 1H), 7.37-7.19 (m, 11H),6.88 (d, 1H, J=7.3 Hz), 6.34 (t, 1H, J=4.5 Hz), 3.34-3.27 (m, 3H),2.94-2.87 (m, 2H), 2.52 (septet, 1H, J=6.9 Hz), 2.46-2.34 (m, 4H), 2.27(t, 2H, J=6.9 Hz), 2.00-1.91 (m, 2H), 1.77-1.69 (m, 2H), 1.69-1.52, (m,5H), 1.30-1.20 (m, 12H); ESMS m/e: 568.4 (M+H)⁺.

EXAMPLE 12

N-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL-2,2-DIPHENYLBUTANAMIDE:Example 12 was prepared from 2,2-diphenylbutanoic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methyl propanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 7.45 (s, 1H), 7.44-7.39 (m, 2H), 7.37-7.28 (m, 8H), 7.27-7.20(m, 3H), 6.89 (d, 1H, J=7.4 Hz), 6.43 (t, 1H, J=4.5 Hz), 3.35-3.27 (m,2H), 2.90-2.82 (m, 2H), 2.51 (septet, 1H, J=6.8 Hz), 2.49-2.35 (m, 4H),2.24 (t, 2H, J=6.3 Hz), 1.89 (t, 2H, J=10.2 Hz), 1.75-1.68 (m, 2H),1.66-1.58 (m, 2H), 1.57-1.45 (m, 2H), 1.24 (d, 6H, J=6.7 Hz), 1.27-1.23(m, 2H); ESMS m/e: 526.3 (M+H)⁺.

EXAMPLE 13

N-[3-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL]-3-METHYLBUTANAMIDE:Example 13 was prepared from diphenylacetyl chloride andN{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-3-methylbutanamideaccording to the procedures described in Scheme 8: ¹H NMR (400 MHz,CDCl₃) δ 10.79-10.51 (br, 1H), 8.85-8.67 (m, 1H), 8.01-7.81 (br, 1H),7.70 (d, 1H, J=7.2 Hz), 7.47-7.14 (m, 11H), 6.89 (d, 1H, J=7.2 Hz), 5.03(s, 1H), 3.53-3.26 (m, 4H), 2.96-2.80 (m, 2H), 2.78-2.52 (m, 3H),2.44-2.14 (m, 2H), 2.26 (d, 2H, J=6.0 Hz), 2.14-1.94 (m, 3H), 1.94-1.76(m, 2H), 1.10 (d, 6H, J=6.4 Hz); ESMS m/e: 512.3 (M+H)⁺; Anal. Calc.(HCl salt) C₃₃H₄₂ClN₃O₂.0.60CH₂Cl₂: C, 67.36; H, 7.27; N, 7.01. Found:C, 67.08; H, 7.57; N, 7.36.

EXAMPLE 14

N-[3-(1-{3-[(2-MESITYL-2-PHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL]PROPANAMIDE: Example 14 was prepared from mesityl(phenyl) acetic acidand N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl} propanamide accordingto the procedures described in Scheme 9: ESMS m/e: 526.3 (M+H)⁺.

EXAMPLE 15

2,2-DIPHENYL-N-(3-{4-[3-(PROPIONYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)BUTANAMIDE: Example 15 was prepared from 2,2-diphenylbutanoic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl] phenyl}propanamide according tothe procedures described in Scheme 10: ¹H NMR (400 MHz, CDCl₃) δ7.43-7.38 (m, 1H), 7.37-7.29 (m, 9H), 7.28-7.21 (m, 4H), 6.90 (d, 1H,J=8.2 Hz), 6.43 (t, 1H, J=4.1), 3.32 (q, 2H, J=6.5 Hz), 2.95-2.89 (m,2H), 2.45 (q, 2H, J=7.9 Hz), 2.43-2.35 (m, 3H), 2.27 (t, 2H, J=6.5 Hz),2.01-1.92 (m, 2H), 1.78-1.59 (m, 6H), 1.24 (t, 3H, J=7.9 Hz), 0.79 (t,3H, J=6.5 Hz); ESMS m/e: 512.3 (M+H)⁺.

EXAMPLE 16

N-{3-[1-(3{[(ETHYLSULFANYL)(DIPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]PHENYL}-2-METHYLPROPANAMIDE: Example 16 was prepared from(ethylsulfanyl) (diphenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to theprocedures described in Scheme 9: ESMS m/e: 658.6 (M+H)⁺.

EXAMPLE 17

N-[3-(1-{3-[(2,2-DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL]CYCLOPROPANECARBOXAMIDE: Example 17 was prepared from diphenylacetylchloride andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamideaccording to the procedures described in Scheme 8: ¹H NMR (400 MHz,CDCl₃) δ 9.26-9.09 (br, 1H), 8.12-7.91 (br, 1H), 7.69 (d, 1H, J=7.2 Hz),7.63-7.42 (br, 1H), 7.43-7.12 (m, 11H), 6.88 (d, 1H, J=7.2 Hz), 5.03 (s,1H), 3.53-3.27 (m, 4H), 2.99-2.84 (m, 2H), 2.84-2.58 (m, 3H), 2.40-2.16(m, 2H), 2.16-1.98 (m, 2H), 1.98-1.83 (m, 2H), 1.78-1.64 (m, 1H),1.10-0.97 (m, 2H), 0.90-0.76 (m, 2H); ESMS m/e: 496.3 (M+H)⁺.

EXAMPLE 18

N-[3-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL]-2,2-DIMETHYLPROPANAMIDE:Example 18 was prepared from diphenylacetyl chloride andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2,2-di methylpropanamideaccording to the procedures described in Scheme 8: ¹H NMR (400 MHz,CDCl₃) δ 7.51-7.41 (s, 1H), 7.34-7.10 (m, 13H), 6.99-6.80 (m, 2H), 4.81(s, 1H), 3.40-3.26 (m, 2H), 2.96-2.78 (m, 2H), 2.50-2.25 (m, 3H),1.98-1.82 (m, 2H), 1.79-1.68 (m, 2H), 1.68-1.45 (m, 4H), 1.23 (s, 9H);ESMS m/e: 512.3 (M+H)⁺.

EXAMPLE 19

N-[3-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL]-3,3-DIMETHYLBUTANAMIDE:Example 19 was prepared from diphenylacetyl chloride andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-3,3-dimethylbutanamideaccording procedures described in Scheme 8: ¹H NMR (400 MHz, CDCl₃) δ10.73-10.50 (br, 1H), 8.63-8.48 (m, 1H), 7.97-7.77 (br, 1H), 7.70 (d,1H, J=7.2 Hz), 7.45-7.11 (m, 11H), 6.89 (d, 1H, J=7.2 Hz), 5.01 (s, 1H),3.46-3.26 (m, 4H), 2.97-2.77 (m, 2H), 2.77-2.50 (m, 3H), 2.42-2.17 (m,2H), 2.25 (s, 2H), 2.14-1.94 (m, 2H), 1.93-1.78 (m, 2H), 1.00 (s, 9H);ESMS m/e: 526.4 (M+H)⁺; Anal. Calc. (HCl salt) C₃₄H₄₄ClN₃O₂.0.31CHCl₃:C, 68.77; H, 7.45; N, 7.01. Found: C, 68.51; H, 7.40; N, 7.39.

EXAMPLE 20

N-[3-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)-4-METHOXYPHENYL]-2-METHYLPROPANAMIDE: Example 20 was prepared from diphenylacetyl chloride andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methoxyphenyl}-2-methylpropanamideaccording to the procedures described in Scheme 8: ESMS m/e: 528.3(M+H)⁺.

EXAMPLE 21

N-{3-[1-(3-{[2,2-BIS(4-FLUOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]PHENYL}PROPANAMIDE: Example 21 was prepared frombis(4-fluorophenyl)acetic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl] phenyl}propanamide according tothe procedures described in Scheme 10: ESMS m/e: 520.3 (M+H)⁺.

EXAMPLE 22

N-[3-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)-4-METHOXYPHENYL]BUTANAMIDE: Example 22 was prepared from diphenyl acetyl chloride andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methoxyphenyl}butanamideaccording to the procedures described in Scheme 8: ESMS m/e: 528.4(M+H)⁺.

EXAMPLE 23

N-{3-[1-(3-{[BIS(4-FLUOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]-4-METHOXYPHENYL}-2-METHYLPROPANAMIDE:Example 23 was prepared from bis(4-fluorophenyl)acetic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]methoxyphenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ESMS m/e: 564.4(M+H)⁺.

EXAMPLE 24

N-[3-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)-4-FLUOROPHENYL]-2-METHYLPROPANAMIDE:Example 24 was prepared from diphenylacetyl chloride andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamideaccording to the procedures described in Scheme 8: ¹H NMR (400 MHz,CDCl₃) δ 7.95 (s, 1H), 7.47 (dd, 1H, J=2.4, 6.4 Hz), 7.34-7.21 (m, 11H),7.06 (t, 1H, J=4.8 Hz), 6.91 (t, 1H, J=10.0 Hz), 4.90 (s, 1H), 3.38 (dd,2H, J=6.0, 11.6 Hz), 2.90-2.87 (m, 2H), 2.74 (m, 1H), 2.50 (m, 1H), 2.36(t, 2H, J=6.8 Hz), 1.96 (dt, 2H, J=2.8, 12.0 Hz), 1.73-1.62 (m, 6H),1.20 (d, 6H, J=6.8 Hz); ESMS m/e: 516.3 (M+H)⁺.

EXAMPLE 25

N-[3-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}PIPERIDINYL)-4-FLUOROPHENYL]BUTANAMIDE: Example 25 was prepared from diphenylacetyl chloride andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl} butanamideaccording to the procedures described in Scheme 8: ¹H NMR (400 MHz,CDCl₃) δ 7.71 (s, 1H), 7.39 (dd, 1H, J=2.8, 6.8 Hz), 7.33-7.21 (m, 11H),7.00 (t, 1H, J=5.6 Hz), 6.92 (t, 1H, J=9.2 Hz), 4.89 (s, 1H), 3.38 (dd,2H, J=6.4, 12.0 Hz), 2.91-2.88 (m, 2H), 2.74 (m, 1H), 2.36 (t, 2H, J=6.4Hz), 2.29 (t, 2H, J=7.6 Hz), 1.97 (dt, 2H, J=2.4, 11.6 Hz), 1.77-1.62(m, 8H), 0.97 (t, 3H, J=7.2 Hz); ESMS m/e: 516.3 (M+H)⁺.

EXAMPLE 26

N-{3-[1-(3-{[BIS(4-FLUOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]-4-METHOXYPHENYL}BUTANAMIDE:Example 26 was prepared from bis(4-fluorophenyl) acetic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methoxyphenyl}butanamideaccording to the procedures described in Scheme 9: ESMS m/e: 564.4(M+H)⁺.

EXAMPLE 27

N-{3-[1-(3-{[2,2-BIS(4-FLUOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]PHENYL}BUTANAMIDE: Example 27 was prepared from bis(4-fluorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl] phenyl}butanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 8.14 (s, 1H), 7.69 (t, 1H, J=5.2 Hz), 7.52 (s, 1H), 7.38 (d,1H, J=8.0 Hz), 7.30-7.27 (m, 4H), 7.20 (t, 1H, J=8.0 Hz), 7.00-4.95 (m,4H), 6.89 (d, 1H, J=8.0 Hz), 4.90 (s, 1H), 3.37 (dd, 2H, J=6.0, 11.6Hz), 3.05 (d, 2H, J=11.2 Hz), 2.55 (t, 2H, J=6.8 Hz), 2.49 (m, 1H), 2.33(t, 2H, J=7.2 Hz), 2.17 (m, 2H), 1.79-1.69 (m, 8H), 0.97 (t, 3H, J=7.6Hz); ESMS m/e: 534.4 (M+H)⁺.

EXAMPLE 28

N-(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)-2,2-bis(4-fluorophenyl)acetamide:Example 28 was prepared from bis(4-fluorophenyl)acetic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl] phenyl}acetamide according to theprocedures described In Scheme 10: ¹H NMR (400 MHz, CDCl₃) δ 8.25 (s,1H), 7.83 (br s, 1H), 7.41-7.85 (m, 12H), 4.90 (s, 1H), 3.36 (dd, 2H,J=5.6, 12.0 Hz), 3.18 (d, 2H, J=11.6 Hz), 2.69 (t, 2H, J=6.4 Hz), 2.53(m, 1H), 2.34 (m, 2H), 2.15 (s, 3H), 1.96-1.79 (m, 6H); ESMS m/e: 506.4(M+H)⁺.

EXAMPLE 29

N-{6-[1-(3-{[BIS(4-FLUOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]-2-PYRIDINYL}-2-METHYLPROPANAMIDE:Example 29 was prepared from bis(4-fluorophenyl)acetic acid andN-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 8.06 (d, 1H, J=8.4 Hz), 7.99 (m, 1H), 7.84 (s, 1H), 7.63 (t,1H, J=8.0 Hz), 7.39-7.32 (m, 4H), 7.03-4.97 (m, 4H), 6.87 (d, 1H, J=7.6Hz), 4.91 (s, 1H), 3.39 (dd, 2H, J=5.2, 11.2 Hz), 3.07 (d, 2H, J=11.6Hz), 2.62 (m, 1H), 2.55 (t, 2H, J=6.4 Hz), 2.34 (m, 1H), 2.16 (t, 2H,J=11.2 Hz), 1.93-1.73 (m, 6H), 1.16 (d, 6H, J=6.8 Hz); ESMS m/e: 535.4(M+H)⁺.

EXAMPLE 30

N-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-2,2-DIPHENYLPROPANAMIDE:Example 30 was prepared from 2,2-diphenylpropanoic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl] phenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 7.46 (s, 1H), 7.42 (s, 1H), 7.39-7.18 (m, 12H), 6.89 (d, 1H,J=7.7 Hz), 6.23 (m, 1H), 3.35 (q, 2H, J=6.4), 2.85 (d, 2H, J=10.8 Hz),2.5 (quintet, 1H, J=7.4 Hz), 2.45-2.36 (m, 1H), 2.28 (t, 2H, J=6.4 Hz),1.99 (s, 3H), 1.91-1.82 (m, 2H), 1.75-1.68 (m, 2H), 1.65 (t, 2H, J=6.4Hz), 1.60-1.47 (m, 2H), 1.23 (d, 6H, J=7.0 Hz); ESMS m/e: 512.4 (M+H)⁺.

EXAMPLE 31

1-(4-CHLOROPHENYL)-N-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)CYCLOPENTANECARBOXAMIDE: Example 31 was prepared from1-(4-chlorophenyl)cyclopentanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 7.45-7.42 (m, 1H), 7.33-7.24 (m, 7H), 6.94 (d, 1H, J=7.1 Hz),6.58-6.52 (m, 1H), 3.26 (q, 2H, J=6.1 Hz), 2.90 (d, 2H, J=10.8 Hz),2.56-2.40 (m, 4H), 2.29 (t, 2H, J=6.3 Hz), 2.03-1.87 (m, 6H), 1.83-1.76(m, 4H), 1.60 (dd, 4H, J=6.8, 4.6 Hz), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e:510.4 (M+H)⁺.

EXAMPLE 32

N-{3-[1-(3-{[BIS(4-FLUOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]-4-METHYLPHENYL}-2-METHYLPROPANAMIDE:Example 32 was prepared from bis(4-fluorophenyl)acetic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 8.09 (s, 1H), 7.98 (s, 1H), 7.59 (d, 1H, J=1.8 Hz), 7.54-7.51(m, 1H), 7.32 (m, 3H), 7.21-7.18 (m, 1H), 6.99-6.94 (m, 5H), 4.87 (s,1H), 3.36 (q, 2H, J=5.8 Hz), 2.92-2.97 (m, 2H), 2.68-2.58 (m, 1H), 2.5(quintet, 1H, J=7.2 Hz), 2.37 (t, 2H, J=5.7 Hz), 2.25 (s, 3H), 2.01-1.92(m, 2H), 1.71-1.52 (m, 6H), 1.16 (d, 6H, J=7.2 Hz); ESMS m/e: 548.4(M+H)⁺.

EXAMPLE 33

N-[3-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)-2-METHYLPHENYL]-2-METHYLPROPANAMIDE: Example 33 was prepared from diphenylacetyl chloride and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-2-methylphenyl}-2-methylpropanamide according to the procedures described inScheme 8: ¹H NMR (400 MHz, CDCl₃) δ 7.49 (d, 1H, J=8.0 Hz), 7.35-7.19(m, 11H), 7.09-7.02 (m, 3H), 4.90 (s, 1H), 3.41 (dd, 2H, J=5.6, 11.6Hz), 2.99 (d, 2H, J=12.8 Hz), 2.72 (m, 1H), 2.59 (m, 1H), 2.43 (t, 2H,J=6.4 Hz), 2.19 (s, 3H), 2.06-2.00 (m, 2H), 1.75-1.60 (m, 6H), 1.30 (d,6H, J=6.8 Hz); ESMS m/e: 512.5 (M+H)⁺.

EXAMPLE 34

N-{3-[1-(3-{[BIS(4-METHYLPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]PHENYL}-2-METHYLPROPANAMIDE: Example 34 was prepared frombis(4-methylphenyl)acetic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl] phenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 7.50 (s, 1H), 7.29 (d, 2H, J=6.1 Hz), 7.13 (m, 8H), 6.93 (d,1H, J=7.5 Hz), 6.83-6.78 (m, 1H), 7.27-7.21 (m, 1H), 4.81 (s, 1H),3.40-3.34 (m, 2H), 2.91 (d, 2H, J=11.6 Hz), 2.53-2.41 (m, 2H), 2.36 (t,2H, J=6.6 Hz), 2.29 (s, 6H), 1.99-1.88 (m, 2H), 1.78 (d, 3H, J=12.9 Hz),1.67 (t, 2H, J=6.6 Hz), 1.62-1.56 (m, 1H), 1.24 (d, 6H, J=6.8 Hz); ESMSm/e: 526.4 (M+H)⁺.

EXAMPLE 35

N-{3-[1-(3-{[bis(4-fluorophenyl)acetyl]amino}propyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamide:Example 35 was prepared from bis(4-fluorophenyl)acetic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 7.58 (dd, 1H, J=2.8, 6.4 Hz), 7.53 (s, 1H), 7.49 (br s, 1H),7.31-6.92 (m, 10H), 4.81 (s, 1H), 3.40 (dd, 2H, J=5.6, 11.2 Hz), 2.93(d, 2H, J=11.6 Hz), 2.76 (m, 1H), 2.49 (m, 1H), 2.42 (t, 2H, J=6.0 Hz),2.02-1.96 (m, 2H), 1.77 (d, 2H, J=11.6 Hz), 1.69-1.62 (m, 4H), 1.22 (d,6H, J=6.8 Hz); ESMS m/e: 552.3 (M+H)⁺.

EXAMPLE 36

1-(4-FLUOROPHENYL)-N-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)CYCLOPENTANECARBOXAMIDE: Example 36 was prepared from1-(4-fluorophenyl)cyclopentanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 7.53 (s, 1H), 7.33 (dd, 2H, J=5.8, 3.6 Hz,), 7.29-7.26 (m, 2H),7.25-7.20 (m, 1H), 7.02-6.95 (m, 2H), 6.93 (d, 1H, J=7.1 Hz), 6.54-6.49(m, 1H), 3.26 (q, 2H, J=6.5 Hz), 3.22-3.14 (m, 1H), 2.90 (d, 1H, J=12.0Hz), 2.55-2.37 (m, 4H), 2.29 (t, 2H, J=6.5 Hz), 2.06 (s, 4H), 2.00-1.90(m, 3H), 1.82-1.75 (m, 4H), 1.73-1.66 (m, 3H), 1.65-1.57 (m, 4H), 1.25(d, 6H, J=6.7 Hz); ESMS m/e: 494.3 (M+H)⁺; Anal. Calc. forC₃₀H₄₀FN₃O₂.0.10CHCl₃.0.650DMF: C, 70.92; H, 8.27; N, 8.64. Found: C,70.83; H, 8.11; N, 8.93.

EXAMPLE 37

2-(4-CHLOROPHENYL)-N-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)PROPANAMIDE: Example 37 was prepared from2-(4-chlorophenyl)propanoic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 7.61 (d, 2H, J=6.5 Hz), 7.26 (s, 6H), 7.05-6.99 (m, 1H), 6.94(d, 1H, J=7.1 Hz), 3.37-3.25 (m, 2H), 2.89 (d, 1H, J=9.6 Hz), 2.57-2.43(m, 2H), 2.37 (t, 2H, J=6.1 Hz), 2.22-2.16 (m, 2H), 2.00-1.91 (m, 2H),1.89-1.77 (m, 2H), 1.69-1.58 (m, 4H), 1.48 (d, 3H, J=7.0 Hz), 1.24 (d,6H, J=7.0 Hz); ESMS m/e: 470.3 (M+H)⁺.

EXAMPLE 38

1-(2-CHLORO-4-FLUOROPHENYL)-N-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)CYCLOPENTANECARBOXAMIDE:Example 38 was prepared from1-(2-chloro-4-fluorophenyl)cyclopentanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 7.58(s, 1H), 7.52 (s, 1H), 7.45-7.36 (m, 1H), 7.34-7.29 (m,1H), 7.23 (t, 1H, J=8.0 Hz), 7.17-7.13 (m, 1H), 6.95-6.90 (m, 2H),6.00-5.94 (m, 1H), 3.30 (q, 2H, J=6.4 Hz), 2.92-2.84 (m, 2H), 2.57-2.38(m, 3H), 2.47-2.39 (m, 1H), 2.31 (t, 1H, J=7.2 Hz), 1.95-1.73 (m, 7H),1.68-1.48 (m, 8H), 1.24 (d, 6H, J=7.2 Hz); ESMS m/e: 528.3 (M+H)⁺.

EXAMPLE 39

N-{3-[1-(3-{[(3,4-DICHLOROPHENYL)(METHOXY)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]PHENYL}-2-METHYLPROPANAMIDE:Example 39 was prepared from (3,4-dichlorophenyl)(methoxy)acetic acidand N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 8.02-7.94 (m, 1H), 7.54 (d, 2H, J=10.1 Hz), 7.41 (d, 1H, J=8.5Hz), 7.34-7.19 (m, 4H), 6.97 (d, 1H, J=7.0 Hz), 4.56 (s, 1H), 3.83 (s,3H), 3.09-3.01 (m, 2H), 2.55-2.39 (m, 4H), 2.17 (s, 1H), 2.08-1.95 (m,3H), 1.91-1.77 (m, 4H), 1.74-165 (m, 2H), 1.22 (d, 6H, J=6.6 Hz); ESMSm/e: 520.2 (M+H)⁺.

EXAMPLE 40

1-(4-FLUOROPHENYL)-N-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)CYCLOHEXANECARBOXAMIDE: Example 40 was prepared from1-(4-fluorophenyl)cyclohexanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl] phenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 7.56 (s, 2H), 7.42-7.36 (m, 2H), 7.30-7.20 (m, 2H), 7.05-6.96(m, 3H), 6.85-6.79 (m, 1H), 3.28 (q, 2H, J=6.3 Hz), 2.95-2.87 (m, 2H),2.57-2.41 (m, 2H), 2.36-2.28 (m, 4H), 2.06 (s, 1H), 1.96-1.84 (m, 4H),1.83-1.75 (m, 2H), 1.71-1.54 (m, 9H), 1.24 (d, 6H, J=7.1 Hz); ESMS m/e:508.3 (M+H)⁺.

EXAMPLE 41

1-(2,4-DICHLOROPHENYL-N-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)CYCLOPROPANECARBOXAMIDE: Example 41 was prepared from1-(2,4-dichlorophenyl)cyclopropanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl] phenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 7.67 (s, 1H), 7.49 (s, 1H), 7.44 (d, 1H, J=2.0 Hz), 7.35 (s,1H), 7.28-7.19 (m, 3H), 6.92 (d, 1H, J=7.6 Hz), 5.69-5.62 (m, 1H), 3.26(q, 2H, J=6.7 Hz), 2.89-2.82 (m, 2H), 2.54 (quintet, 1H, J=6.7 Hz),2.47-2.37 (m, 1H), 2.32-2.26 (m, 3H), 1.97-1.88 (m, 2H), 1.79-1.69 (m,4H), 1.66-1.56 (m, 4H), 1.24 (d, 6H, J=6.7 Hz), 1.05-1.01 (m, 1H); ESMSm/e: 516.2 (M+H)⁺; Anal. Calc. for C₂₈H₃₅Cl₂N₃O₂.0.048 CHCl₃: C, 64.51;H, 6.76; N, 8.05. Found: C, 64.51; H, 6.60; N, 8.15.

EXAMPLE 42

2-(4-FLUOROPHENYL)-N-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)PROPANAMIDE: Example 42 was prepared from 2-(4-fluorophenyl)propanoic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methyl propanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 7.58 (s, 2H), 7.32-7.22 (m, 4H), 7.01-6.92 (m, 3H), 6.90-6.83(m, 1H), 3.50 (q, 1H, J=7.1 Hz), 3.39-3.26 (m, 2H), 2.93-2.86 (m, 1H),2.55-2.42 (m, 2H), 2.40-2.34 (m, 2H), 2.16 (s, 1H), 2.01-1.91 (m, 2H),1.89-1.77 (m, 2H), 1.72-1.54 (m, 4H), 1.49 (d, 3H, J=7.0 Hz), 1.24 (d,6H, J=7.0 Hz); ESMS m/e: 454.3 (M+H)⁺; Anal. Calc. forC₂₇H₃₆FN₃O₂.1.1CH₃OH: C, 69.04; H, 8.33; N, 8.60. Found: C, 69.06; H,8.61; N, 8.79.

EXAMPLE 43

1-(4-CHLOROPHENYL)-N-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)CYCLOBUTANECARBOXAMIDE: Example 43 was prepared from1-(4-chlorophenyl)cyclobutanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 7.56 (s, 1H), 7.41 (s, 1H), 7.34-7.21 (m, 6H), 6.93 (s, 1H),6.48 (s, 1H), 3.31-3.24 (m, 2H), 2.94-2.86 (m, 2H), 2.86-2.76 (m, 2H),2.57-2.37 (m, 4H), 2.33-2.26 (m, 2H), 2.12-2.02 (m, 1H), 1.97-1.87 (m,3H), 1.82 (s, 1H), 1.79 (s, 1H), 1.70-1.56 (m, 4H), 1.24 (d, 6H, J=7.2Hz); ESMS m/e: 496.3 (M+H)⁺; Anal. Calc. for C₂₉H₃₈ClN₃O₂.0.550CHCl₃: C,63.18; H, 6.92; N, 7.48. Found: C, 63.22; H, 6.90; N, 7.48.

EXAMPLE 44

1-(4-CHLOROPHENYL)-N-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)CYCLOPROPANECARBOXAMIDE: Example 44 was prepared from1-(4-chlorophenyl)cyclopropanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 7.47 (s, 1H), 7.40 (s, 1H), 7.36-7.30 (m, 5H), 7.27-7.20 (m,1H), 6.93 (d, 1H, J=7.6 Hz), 5.70-5.63 (m, 1H), 3.24 (q, 2H, J=6.6 Hz),2.84 (d, 2H, J=11.4 Hz), 2.52 (quintet, 1H, J=7.2 Hz), 2.47-2.37 (m,1H), 2.26 (t, 2H, J=7.2 Hz), 1.92 (t, 2H, J=11.6 Hz), 1.75 (d, 2H,J=12.5 Hz), 1.65-1.53 (m, 6H), 1.25 (d, 6H, J=7.2 Hz), 1.00 (q, 2H,J=2.9 Hz); ESMS m/e: 482.3 (M+H)⁺; Anal. Calc. for C₂₈H₃₆ClN₃O₂.0.540CH₂Cl₃: C, 64.93; H, 7.08; N, 7.96. Found: C, 65.00; H, 7.22; N, 7.81.

EXAMPLE 45

1-(4-CHLOROPHENYL)-N-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)CYCLOHEXANECARBOXAMIDE: Example 45 was prepared from1-(4-chlorophenyl) cyclohexanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methyl propanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 7.57 (s, 1H), 7.52 (s, 1H), 7.38-7.35 (m, 2H), 7.30-7.21 (m,4H), 6.93 (d, 1H, J=7.2 Hz), 6.88-6.83 (m, 1H), 3.28 (q, 2H, J=5.6 Hz),2.95-2.88 (m, 2H), 2.56-2.41 (m, 2H), 2.35-2.26 (m, 3H), 2.07 (s, 1H),1.96-1.84 (m, 4H), 1.83-1.76 (m, 2H), 1.70-1.53 (m, 10H), 1.24 (d, 6H,J=7.1 Hz); ESMS m/e: 524.3 (M+H)⁺.

EXAMPLE 46

N-(3-{4-[4-FLUORO-3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-2-(4-FLUOROPHENYL)PROPANAMIDE:Example 46 was prepared from 2-(4-fluorophenyl)propanoic acid andN-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 8.38-8.23 (m, 1H), 7.48-7.27 (m, 3H), 7.13-6.94 (m, 4H),6.94-6.82 (m, 1H), 3.62-3.46 (m, 1H), 3.41-3.26 (m, 2H), 3.17-3.03 (m,1H), 3.02-2.91 (m, 1H), 2.67-2.35 (m, 4H), 2.24-1.97 (m, 2H), 1.95-1.62(m, 6H), 1.49 (d, 3H, J=7.2 Hz), 1.27 (d, 6H, J=6.8 Hz); ESMS m/e: 472.4(M+H)⁺.

EXAMPLE 47

1-(4-CHLOROPHENYL)-N-(3-{4-[4-FLUORO-3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)CYCLOPROPANECARBOXAMIDE:Example 47 was prepared from 1-(4-chlorophenyl)cyclopropanecarboxylicacid andN-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 8.32-8.18 (m, 1H), 7.43-7.25 (m, 5H), 7.08-6.93 (m, 1H),6.93-6.79 (br, 1H), 5.74-5.59 (br, 1H), 3.35-3.15 (m, 2H), 3.93-2.75 (m,2H), 2.65-2.49 (m, 1H), 2.49-2.34 (m, 1H), 2.34-2.19 (m, 2H), 2.00-1.83(m, 2H), 1.82-1.68 (m, 2H), 1.68-1.48 (m, 4H), 1.36-1.17 (m, 2H), 1.27(d, 6H, J=6.8 Hz), 1.0 (s, 2H); ESMS m/e: 500.3 (M+H)⁺; Anal. Calc. for(HCl salt) C₂₈H₃₆Cl₂FN₃O₂.0.45CHCl₃: C, 57.85; H, 6.22; N, 7.11. Found:C, 57.61; H, 6.37; N, 7.30.

EXAMPLE 48

N-{5-[1-(3-{[BIS(4-FLUOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]-2-FLUOROPHENYL}2-METHYLPROPANAMIDE: Example 48 was prepared frombis(4-fluorophenyl) acetic acid andN-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ESMS m/e: 552.3(M+H)⁺.

EXAMPLE 49

2-(4-CHLOROPHENYL)-N-(3-{4-[4-FLUORO-3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-2-METHYLPROPANAMIDE:Example 49 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acidandN-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 8.34-8.20 (m, 1H), 7.46-7.14 (m, 5H), 7.10-6.95 (m, 1H),6.92-6.77 (br, 1H), 6.74-6.59 (br, 1H), 3.39-3.25 (m, 2H), 3.00-2.82 (m,2H), 2.67-2.51 (m, 1H), 2.51-2.40 (m, 1H), 2.40-2.27 (m, 2H), 2.03-1.86(m, 2H), 1.85-1.71 (m, 2H), 1.71-1.57 (m, 4H), 1.56 (s, 6H), 1.27 (d,6H, J=6.8 Hz); ESMS m/e: 502.3 (M+H)⁺.

EXAMPLE 50

N-{6-[1-(3-{[BIS(4-CHLOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]-2-PYRIDINYL}-2-METHYLPROPANAMIDE:Example 50 was prepared from bis(4-chlorophenyl)acetic acid andN-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 8.06 (d, 1H, J=8.0 Hz), 7.96 (br s, 1H), 7.77 (s, 1H), 7.64 (t,1H, J=8.4 Hz), 7.31-7.26 (m, 8H), 6.88 (dd, 1H, J=0.8, 7.6 Hz), 4.84 (s,1H), 3.39 (dd, 2H, J=5.6, 11.6 Hz), 2.99 (d, 2H, J=11.6 Hz), 2.59 (m,1H), 2.47 (t, 2H, J=6.0 Hz), 2.28 (m, 1H), 2.07-2.00 (m, 2H), 1.89 (dd,2H, J=2.0, 12.4 Hz), 1.76-1.67 (m, 4H), 1.14 (d, 6H, J=6.8 Hz); ESMSm/e: 567.3 (M+H)⁺.

EXAMPLE 51

N-(3-{4-[4-FLUORO-3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-2,2-DIPHENYLPROPANAMIDE:Example 51 was prepared from 2,2-diphenylpropanoic acid andN-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 8.27-8.13 (m, 1H), 8.04 (s, 1H), 7.62 (s, 1H), 7.50-7.39 (m,1H), 7.39-7.16 (m, 7H), 7.12-6.90 (m, 2H), 6.79-6.60 (br, 1H), 4.94-4.61(br, 1H), 3.60-3.22 (m, 4H), 2.89-2.76 (m, 2H), 2.76-2.55 (m, 4H),2.55-2.34 (m, 3H), 2.14-1.82 (m, 3H), 2.00 (s, 3H), 1.26 (d, 6H, J=6.4Hz); ESMS m/e: 530.4 (M+H)⁺; Anal. Calc. for (HCl salt)C₃₃H₄₁ClFN₃O₂.0.24CHCl₃.0.96H₂O: C, 65.23; H, 7.11; N, 6.86. Found: C,64.96; H, 7.36; N, 6.87.

EXAMPLE 52

N-{3-[1-(3-{[BIS(4-CHLOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]-4-METHYLPHENYL}-2-METHYLPROPANAMIDE:Example 52 was prepared from bis(4-chlorophenyl)acetic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 7.65 (s, 1H), 7.62 (d, 1H, J=2.4 Hz), 7.53 (t, 1H, J=4.8 Hz),7.28-7.22 (m, 8H), 7.12 (dd, 1H, J=2.0, 8.4 Hz), 7.03 (d, 1H, J=8.0 Hz),4.80 (s, 1H), 3.36 (dd, 2H, J=6.0, 11.6 Hz), 2.91 (d, 2H, J=14.0 Hz),2.64 (m, 1H), 2.47 (m, 1H), 2.38 (t, 2H, J=5.6 Hz), 2.24 (s, 3H),2.00-1.93 (m, 2H), 1.70-1.56 (m, 6H), 1.16 (d, 6H, J=7.2 Hz); ESMS m/e:580.3 (M+H)⁺.

EXAMPLE 53

N-{3-[1-(3-{[2,2-BIS(4-CHLOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]PHENYL}BUTANAMIDE: Example 53 was prepared frombis(4-chlorophenyl)acetic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to theprocedures described in Scheme 10: ¹H NMR (400 MHz, CDCl₃) δ 7.67 (s,1H), 7.58 (s, 1H), 7.49 (br s, 1H), 7.28-7.21 (m, 10H), 6.91 (m, 1H),4.77 (s, 1H), 3.38 (dd, 2H, J=6.0, 11.6 Hz), 2.93 (d, 2H, J=11.6 Hz),2.46 (m, 1H), 2.41 (t, 2H, J=6.0 Hz), 2.31 (t, 2H, J=7.2 Hz), 1.96 (dt,2H, J=1.6, 12.0 Hz); 1.82-1.66 (m, 6H), 1.58-1.54 (m, 2H), 0.98 (t, 3H,J=7.6 Hz); ESMS m/e: 566.3 (M+H)⁺.

EXAMPLE 54

N-{3-[1-(3-{[BIS(4-CHLOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]-4-FLUOROPHENYL}-2-METHYLPROPANAMIDE:Example 54 was prepared from bis(4-chlorophenyl)acetic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 7.62-7.57 (m, 3H), 7.27 (s, 8H), 7.23-7.19 (m, 1H), 6.94 (dd,1H, J=8.8, 10.0 Hz), 4.78 (s, 1H), 3.39 (dd, 2H, J=6.0, 11.6 Hz), 2.93(d, 2H, J=11.6 Hz), 2.77 (m, 1H), 2.48 (m, 1H), 2.42 (t, 2H, J=6.0 Hz),1.99 (dt, 2H, J=1.6, 11.6 Hz), 1.77 (d, 2H, J=11.2 Hz), 1.69-1.61 (m,4H), 1.22 (d, 6H, J=6.8 Hz); ESMS m/e: 584.2 (M+H)⁺.

EXAMPLE 55

N-(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-2,2-BIS(4-CHLOROPHENYL)ACETAMIDE:Example 55 was prepared from bis(4-chlorophenyl)acetic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide accordingprocedures described in Scheme 10: ¹H NMR (400 MHz, CDCl₃) δ 7.48 (s,1H), 7.39 (br s, 1H), 7.31-7.22 (m, 11H), 6.94-6.92 (m, 1H), 4.76 (s,1H), 3.39 (dd, 2H, J=6.4, 12.0 Hz), 2.97 (d, 2H, J=10.0 Hz), 2.49 (m,1H), 2.44 (t, 2H, J=6.4 Hz), 2.17 (s, 3H), 2.05-1.99 (m, 2H), 1.83 (d,2H, J=13.2 Hz), 1.71 (m, 2H), 1.61 (m, 2H); ESMS m/e: 538.3 (M+H)⁺.

EXAMPLE 56

N-[5-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)-2-FLUOROPHENYL]-2-METHYLPROPANAMIDE:Example 56 was prepared from diphenylacetyl chloride andN-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2-methylpropanamideaccording to the procedures described in Scheme 8: ¹H NMR (400 MHz,CD₃OD,) δ 7.80-7.64 (m, 1H), 7.37-7.09 (m, 12H), 7.08-6.98 (m, 1H),6.98-6.88 (br, 1H), 4.90 (s, 1H), 3.47-3.33 (m, 2H), 3.33-3.18 (m, 2H),3.01-2.81 (m, 4H), 2.81-2.69 (m, 1H), 2.69-2.54 (m, 1H), 2.10-1.66 (m,6H), 1.10 (d, 6H, J=6.4 Hz); ESMS m/e: 516.4 (M+H)⁺. Anal. Calc. For(HCl salt) C₃₂H₃₉ClFN₃O₂.0.16CHCl₃: C, 67.68; H, 6.92; N, 7.36. Found:C, 67.43; H, 6.85; N, 7.17.

EXAMPLE 57

N-{3-[1-(3-{[2,2-BIS(4-CHLOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]PHENYL}PROPANAMIDE: Example 57 was prepared frombis(4-chlorophenyl)acetic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according tothe procedures described in Scheme 10: ESMS m/e: 552.2 (M+H)⁺.

EXAMPLE 58

1-(4-CHLOROPHENYL)-N-(3-{4-[3-PROPIONYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)CYCLOBUTANECARBOXAMIDE: Example 58 was prepared from1-(4-chlorophenyl)cyclobutanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl} propanamide according tothe procedures described in Scheme 10: ESMS m/e: 482.3 (M+H)⁺.

EXAMPLE 59

2-METHYL-N-[3-(1-{3-[(TRIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL]PROPANAMIDE: Example 59 was prepared from triphenylacetic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 7.40 (d, 2H, J=10.8 Hz), 7.32-7.17 (m, 17H), 6.87 (d, 1H, J=7.7Hz), 6.32-6.26 (m, 1H), 3.41 (q, 2H, J=6.0 Hz), 2.83 (d, 2H, J=10.5 Hz),2.48 (quintet, 1H, J=6.7 Hz), 2.43-2.33 (m, 1H), 2.26 (t, 2H, J=6.7 Hz),1.89 (t, 2H, J=11.5 Hz), 1.73-1.62 (m, 4H), 1.56-1.44 (m, 2H), 1.22 (d,6H, J=6.7 Hz); ESMS m/e: 574.3 (M+H)⁺; Anal. Calc. forC₃₈H₄₃N₃O₂.0.730CHCl₃: C, 70.38; H, 6.67; N, 6.36. Found: C, 70.42; H,6.57; N, 6.47.

EXAMPLE 60

1-(4-FLUOROPHENYL)-N-(3-{4-[3-(PROPIONYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)CYCLOPENTANECARBOXAMIDE:Example 60 was prepared from 1-(4-fluorophenyl)cyclopentanecarboxylicacid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamideaccording to the procedures described in Scheme 10: ESMS m/e: 480.4(M+H)⁺.

EXAMPLE 61

1-(4-FLUOROPHENYL)-N-(3-{4-[3-(PROPIONYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)CYCLOHEXANECARBOXAMIDE: Example 61 was prepared from1-(4-fluorophenyl)cyclohexanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl} propanamide according tothe procedures described in Scheme 10: ESMS m/e: 494.4 (M+H)⁺.

EXAMPLE 62

1-(4-CHLOROPHENYL)-N-(3-{4-[3-PROPIONYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)CYCLOPENTANECARBOXAMIDE: Example 62 was prepared from1-(4-chlorophenyl)cyclopentanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl} propanamide according tothe procedures described in Scheme 10: ESMS m/e: 496.4 (M+H)⁺.

EXAMPLE 63

1-(4-CHLOROPHENYL-N-(3-{4-[3-(PROPIONYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)CYCLOPROPANECARBOXAMIDE: Example 63 was prepared from1-(4-chlorophenyl)cyclopropanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl} propanamide according tothe procedures described in Scheme 10: ESMS m/e: 468.3 (M+H)⁺.

EXAMPLE 64

2-(4-FLUOROPHENYL)-N-(3-{4-[3-PROPIONYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL) PROPANAMIDE: Example 64 was prepared from2-(4-fluorophenyl)propanoic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according tothe procedures described in Scheme 10: ESMS m/e: 440.4 (M+H)⁺.

EXAMPLE 65

N-[5-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL})-4-PIPERIDINYL)-2-FLUOROPHENYL]BUTANAMIDE: Example 65 was prepared from diphenylacetyl chloride andN-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}butanamideaccording to the procedures described in Scheme 8: ¹H NMR (400 MHz,CDCl₃) δ 8.33-8.18 (m, 1H), 7.49-7.10 (m, 12H), 7.10-6.93 (m, 1H),6.90-6.76 (br, 1H), 4.87 (s, 1H), 3.44-3.28 (m, 2H), 3.06-2.89 (m, 2H),2.56-2.40 (m, 3H), 2.40-2.31 (m, 2H), 2.13-1.93 (m, 2H), 1.86-1.52 (m,8H), 1.01 (t, 3H, J=7.6 Hz); ESMS m/e: 516.6 (M+H)⁺; Anal. Calc. For(HCl salt) C₃₂H₃₉ClFN₃O₂.0.25CHCl₃.1.00H₂O: C, 64.49; H, 6.93; N, 6.99.Found: C, 64.23; H, 7.21; N, 6.99.

EXAMPLE 66

1-(4-FLUOROPHENYL)-N-(3-{4-[6-(ISOBUTYRYLAMINO)-2-pyridinyl]-piperidinyl}propyl)cyclopentanecarboxamide: Example 66 was prepared from 1-(4-fluorophenyl)cyclopentanecarboxylic acid andN-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}2-methylpropanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 8.06 (d, 1H, J=8.4 Hz), 7.79 (s, 1H), 7.64 (t, 1H, J=7.6 Hz),7.38-7.34 (m, 2H), 7.01-6.97 (m, 2H), 6.88 (d, 1H, J=7.2 Hz), 6.53 (brs, 1H), 3.27 (dd, 2H, J=6.0, 12.4 Hz), 2.94 (d, 2H, J=14.0 Hz),2.54-2.48 (m, 4H), 2.32 (t, 2H, J=6.4 Hz), 1.99-1.60 (m, 14H), 1.25 (d,6H, J=7.2 Hz); ESMS m/e: 495.3 (M+H)⁺.

EXAMPLE 67

1-(4-CHLOROPHENYL)-N-(3-{4-[6-(ISOBUTYRYLAMINO)-2-PYRIDINYL]-1-PIPERIDINYL}PROPYL)CYCLOHEXANECARBOXAMIDE: Example 67 was prepared from1-(4-chlorophenyl)cyclohexanecarboxylic acid andN-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 8.06 (d, 1H, J=8.4 Hz), 7.78 (br s, 1H), 7.65 (t, 1H, J=8.0Hz), 7.40-7.38 (m, 2H), 7.30-7.27 (m, 2H), 6.88 (d, 2H, J=7.6 Hz), 3.29(dd, 2H, J=6.0, 11.6 Hz), 2.96 (m, 2H), 2.56-2.49 (m, 2H), 2.36-2.30 (m,4H), 2.00-1.75 (m, 8H), 1.64-1.59 (m, 8H), 1.25 (d, 6H, J=6.8 Hz); ESMSm/e: 525.3 (M+H)⁺.

EXAMPLE 68

1-(4-FLUOROPHENYL)-N-(3-{4-[6-(ISOBUTYRYLAMINO)-2-PYRIDINYL]-1-PIPERIDINYL}PROPYL)CYCLOHEXANECARBOXAMIDE: Example 68 was prepared from1-(4-fluorophenyl)cyclohexanecarboxylic acid andN-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 8.07 (d, 1H, J=8.0 Hz), 7.79 (br s, 1H), 7.66 (t, 1H, J=8.0Hz), 7.45-7.41 (m, 2H), 7.04-7.00 (m, 2H), 6.89 (d, 1H, J=7.6 Hz), 6.85(br s, 1H), 3.30 (dd, 2H, J=6.0, 12.0 Hz), 2.97 (d, 2H, J=11.6 Hz),2.57-2.50 (m, 2H), 2.37-2.32 (m, 4H), 2.01-1.77 (m, 8H), 1.65-1.60 (m,8H), 1.27 (d, 6H, J=7.2 Hz); ESMS m/e: 509.3 (M+H)⁺.

EXAMPLE 69

N-(3-{4-[3-(butyrylamino)phenyl]-1-piperidinyl}propyl)-1-(4-chlorophenyl)cyclopropanecarboxamide: Example 69 was prepared from 1-(4-chlorophenyl)cyclopropanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the proceduresdescribed in Scheme 10: ¹H NMR (400 MHz, CDCl₃) δ 7.53 (s, 1H), 7.45 (s,1H), 7.36-7.34 (m, 5H), 7.24 (t, 1H, J=8.0 Hz), 6.94 (d, 1H, J=7.6 Hz),5.69 (br s, 1H), 3.25 (dd, 2H, J=6.8, 12.8 Hz), 2.87 (d, 2H, J=11.6 Hz),2.44 (m, 1H), 2.35 (t, 2H, J=7.2 Hz), 2.29 (t, 2H, J=6.8 Hz), 1.95 (t,2H, J=11.2 Hz), 1.80-1.74 (m, 4H), 1.63-1.59 (m, 6H), 1.03-1.00 (m, 5H);ESMS m/e: 482.3 (M+H)⁺.

EXAMPLE 70

N-(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-1-(4-FLUOROPHENYL)CYCLOHEXANECARBOXAMIDE: Example 70 was prepared from1-(4-fluorophenyl)cyclohexanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to theprocedures described in Scheme 10: ¹H NMR (400 MHz, CDCl₃) δ 7.47 (m,2H), 7.43-7.39 (m, 20), 7.30-7.27 (m, 2H), 7.04-7.00 (m, 2H), 6.96 (d,1H, J=7.2 Hz), 6.77 (br s, 1H), 3.30 (dd, 2H, J=5.6, 11.6 Hz), 2.95 (d,2H, J=11.6 Hz), 2.49 (m, 1H), 2.34 (t, 4H, J=6.4 Hz), 2.19 (s, 3H),1.99-1.80 (m, 6H), 1.73-1.60 (m, 10H); ESMS m/e: 480.3 (M+H)⁺.

EXAMPLE 71

N-(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-1-(4-CHLOROPHENYL) CYCLOPROPANECARBOXAMIDE: Example 71 was prepared from1-(4-chlorophenyl)cyclopropanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the proceduresdescribed in Scheme 10: ¹H NMR (400 MHz, CDCl₃) δ 7.51 (s, 1H),7.39-7.34 (m, 6H), 7.26 (t, 1H, J=7.2 Hz), 6.96 (d, 1H. J=7.6 Hz), 5.68(br s, 1H), 3.26 (dd, 2H, J=6.8, 12.8 Hz), 2.88 (d, 2H, J=13.2 Hz), 2.45(m, 1H), 2.30 (t, 2H, J=7.2 Hz), 2.19 (s, 3H), 1.96 (t, 2H, J=11.6 Hz),1.78 (d, 2H, J=12.8 Hz), 1.65-1.58 (m, 6H), 1.02 (dd, 2H, J=3.6, 6.8Hz); ESMS m/e: 454.2 (M+H)⁺.

EXAMPLE 72

N-(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-1-(4-FLUOROPHENYL)CYCLOPENTANECARBOXAMIDE: Example 72 was prepared from 1-(4-fluorophenyl)cyclopentanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to theprocedures described in Scheme 10: ¹H NMR (400 MHz, CDCl₃) δ 7.44 (s,1H), 7.38-7.25 (m, 5H), 7.03-6.97 (m, 3H), 6.49 (br s, 1H), 3.29 (dd,2H, J=5.6, 12.0 Hz), 2.98-2.94 (m, 2H), 2.55-2.49 (m, 3H), 2.33 (t, 2H,J=6.8 Hz), 2.20 (s, 3H), 2.01-1.95 (m, 4H), 1.86-0.162 (m, 10H); ESMSm/e: 466.2 (M+H)⁺.

EXAMPLE 73

1-(4-CHLOROPHENYL)-N-(3-{4-[6-(ISOBUTYRYLAMINO)-2-PYRIDINYL]-1-PIPERIDINYL}PROPYL)CYCLOBUTANECARBOXAMIDE: Example 73 was prepared from 1-(4chlorophenyl)cyclobutanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 8.07 (d, 1H, J=8.0 Hz), 7.78 (br s, 1H), 7.66 (t, 1H, J=7.6Hz), 7.37-7.32 (m, 4H), 6.90 (d, 1H, J=7.6 Hz), 6.65 (br s, 1H), 3.30(dd, 2H, J=5.6, 11.6 Hz), 2.98 (d, 2H, J=11.2 Hz), 2.88-2.81 (m, 2H),2.58-2.43 (m, 4H), 2.36 (t, 2H, J=6.4 Hz), 2.10-1.96 (m, 4H), 1.92-1.78(m, 4H), 1.64 (m, 2H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 497.2 (M+H)⁺.

EXAMPLE 74

N-(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-1-(4-CHLOROPHENYL)CYCLOBUTANECARBOXAMIDE: Example 74 was prepared from1-(4-chlorophenyl)cyclobutanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to theprocedures described in Scheme 10: ¹H NMR (400 MHz, CDCl₃) δ 7.55 (s,1H), 7.36-7.26 (m, 7H), 6.97 (d, 1H, J=7.2 Hz), 6.50 (brs, 1H), 3.30(dd, 2H, J=6.0, 12.0 Hz), 2.98-2.95 (m, 2H), 2.87-2.80 (m, 2H),2.53-2.42 (m, 3H), 2.34 (t, 2H, J=6.4 Hz), 2.20 (s, 3H), 2.15-1.82 (m,6H), 1.74-0.161 (m, 4H); ESMS m/e: 468.2 (M+H)⁺.

EXAMPLE 75

N-(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-1-(4-CHLOROPHENYL)CYCLOHEXANECARBOXAMIDE: Example 75 was prepared from 1-(4-chlorophenyl)cyclohexanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to theprocedures described in Scheme 10: ¹H NMR (400 MHz, CDCl₃) δ 7.47 (s,1H), 7.44 (s, 1H), 7.40-7.37 (m, 2H), 7.32-7.25 (m, 4H), 6.96 (d, 1H,J=7.2 Hz), 6.81 (br s, 1H), 3.30 (dd, 2H, J=5.6, 11.6 Hz), 2.94 (d, 2H,J=12.4 Hz), 2.49 (m, 1H), 2.34 (t, 4H, J=6.4 Hz), 2.20 (s, 3H),1.99-1.81 (m, 6H), 1.72-1.55 (m, 10H); ESMS m/e: 496.2 (M+H)⁺.

EXAMPLE 76

1-(4-CHLOROPHENYL)-N-(3-{4-[6-(ISOBUTYRYLAMINO)-2-PYRIDINYL]-1-PIPERIDINYL}PROPYL)CYCLOPROPANECARBOXAMIDE: Example 76 was prepared from1-(4-chlorophenyl)cyclopropanecarboxylic acid andN-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 8.06 (d, 1H, J=8.0 Hz), 7.83 (s, 1H), 7.64 (t, 1H, J=7.6 Hz),7.38-7.33 (m, 4H), 6.89 (d, 1H, J=7.6 Hz), 5.68 (br s, 1H), 3.26 (dd,2H, J=6.0, 12.4 Hz), 2.90 (d, 2H, J=11.6 Hz), 2.58-2.52 (m, 2H), 2.31(t, 2H, J=6.8 Hz), 1.99 (t, 2H, J=12.0 Hz), 1.85 (d, 2H, J=12.8 Hz),1.70-1.59 (m, 6H), 1.28 (d, 6H, J=6.8 Hz), 1.01 (dd, 2H, J=3.6, 6.4 Hz);ESMS m/e: 483.3 (M+H)⁺.

EXAMPLE 77

N-{3-[1-(3-{[2-(4-CHLOROPHENYL)PROPANOYL]AMINO}PROPYL)-4-PIPERIDINYL]PHENYL}BUTANAMIDE: Example 77 was prepared from2-(4-chlorophenyl)propanoic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to theprocedures described in Scheme 10: ¹H NMR (400 MHz, CDCl₃) δ 7.56 (s,1H), 7.41 (s, 1H), 7.30-7.27 (m, 6H), 6.96 (m, 2H), 3.51 (q, 1H, J=7.2Hz), 3.50-3.30 (m, 2H), 3.02 (d, 1H, J=10.8 Hz), 2.92 (d, 1H, J=13.6Hz), 2.50 (m, 1H), 2.41-2.34 (m, 4H), 1.99-1.94 (m, 2H), 1.86-1.58 (m,8H), 1.51 (d, 3H, J=7.2 Hz), 1.02 (t, 3H, J=7.6 Hz); ESMS m/e: 470.3(M+H)⁺.

EXAMPLE 78

N-(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-1-(4-CHLOROPHENYL)CYCLOPENTANECARBOXAMIDE: Example 78 was prepared from 1-(4-chlorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the proceduresdescribed in Scheme 10: ¹H NMR (400 MHz, CDCl₃) δ 7.44 (s, 1H),7.34-7.26 (m, 7H), 6.97 (d, 1H, J=7.6 Hz), 6.54 (br s, 1H), 3.28 (dd,2H, J=5.6, 12.0 Hz), 2.95 (d, 2H, J=12.0 Hz), 2.54-2.48 (m, 3H), 2.33(t, 2H, J=6.8 Hz), 2.20 (s, 3H), 2.00-1.95 (m, 4H), 1.84-1.60 (m, 10H);ESMS m/e: 482.2 (M+H)⁺.

EXAMPLE 79

N-(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-2-(4-CHLOROPHENYL)-2-METHYLPROPANAMIDE: Example 79 was prepared from2-(4-chlorophenyl)-2-methyl propanoic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to theprocedures described in Scheme 10: ¹H NMR (400 MHz, CDCl₃) δ 7.43 (s,2H), 7.34-7.25 (m, 6H), 6.95 (d, 1H, J=7.2 Hz), 6.65 (brs, 1H), 3.33(dd, 2H, J=6.0, 12.0 Hz), 2.92 (d, 2H, J=12.0 Hz), 2.45 (m, 1H), 2.36(t, 2H, J=6.0 Hz), 2.20 (s, 3H), 1.94 (t, 2H, J=12.4 Hz), 1.78 (d, 2H,J=13.2 Hz), 1.65 (m, 2H), 1.57 (s, 6H), 1.55-1.46 (m, 2H); ESMS m/e:456.2 (M+H)⁺.

EXAMPLE 80

N-{3-[1-(3-{[2-(4-CHLOROPHENYL-2-METHYLPROPANOYL]AMINO}PROPYL)-4-PIPERIDINYL]PHENYL}BUTANAMIDE:Example 80 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acidand N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according tothe procedures described in Scheme 9: ESMS m/e: 484.3 (M+H)⁺.

EXAMPLE 81

1-(4-CHLOROPHENYL)-N-(3-{4-[5-(ISOBUTYRYLAMINO)-2-METHYLPHENYL]-1-PIPERIDINYL}PROPYL)CYCLOPENTANECARBOXAMIDE:Example 81 was prepared from 1-(4-chlorophenyl)cyclopentanecarboxylicacid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 7.44 (d, 1H, J=2.0 Hz), 7.37-7.34 (m, 2H), 7.31-7.25 (m, 4H),7.09 (d, 1H, J=8.0 Hz), 6.50 (brs, 1H), 3.29 (dd, 2H, J=6.4, 12.0 Hz),2.92 (d, 2H, J=11.6 Hz), 2.66 (m, 1H), 2.54-2.48 (m, 3H), 2.33-2.29 (m,5H), 2.03-1.94 (m, 4H), 1.83-1.59 (m, 10H), 1.26 (d, 6H, J=6.8 Hz); ESMSm/e: 524.3 (M+H)⁺.

EXAMPLE 82

2-METHYL-N-[6-(1-{3-[(TRIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)-2-PYRIDINYL]PROPANAMIDE:Example 82 was prepared from triphenyl acetic acid andN-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 8.05 (d, 1H, J=8.0 Hz), 7.81 (s, 1H), 7.63 (t, 1H, J=7.6 Hz),7.30-7.24 (m, 15H), 6.84 (d, 1H, J=7.2 Hz), 6.33 (br s, 1H), 3.44 (dd,2H, J=6.4, 12.4 Hz), 2.89 (d, 2H, J=11.6 Hz), 2.57-2.49 (m, 2H), 2.31(t, 2H, J=6.8 Hz), 1.95 (t, 2H, J=12.0 Hz), 1.79-1.58 (m, 6H), 1.27 (d,6H, J=6.8 Hz); ESMS m/e: 575.3 (M+H)⁺.

EXAMPLE 83

N-(3-{4-[6-(ISOBUTYRYLAMINO)-2-PYRIDINYL]-1-PIPERIDINYL}PROPYL-2,2-DIPHENYLPROPANAMIDE:Example 83 was prepared from 2,2-diphenylpropanoic acid andN-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 8.05 (d, 1H, J=8.0 Hz), 7.80 (s, 1H), 7.63 (t, 1H, J=7.6 Hz),7.35-7.24 (m, 10H), 6.85 (d, 1H, J=8.0 Hz), 6.26 (t, 1H, J=4.8 Hz), 3.38(dd, 2H, J=6.4, 12.4 Hz), 2.92-2.89 (m, 2H), 2.55-2.48 (m, 2H), 2.32 (t,2H, J=6.8 Hz), 2.00 (s, 3H), 1.96 (t, 2H, J=11.2 Hz), 1.79 (d, 2H,J=11.6 Hz), 1.72-1.61 (m, 4H), 1.27 (d, 6H, 6.8 Hz); ESMS m/e: 513.3(M+H)⁺.

EXAMPLE 84

1-(4-CHLOROPHENYL)-N-(3-{4-[6-(ISOBUTYRYLAMINO)-2-PYRIDINYL]-1-PIPERIDINYL}PROPYL)CYCLOPENTANECARBOXAMIDE:Example 84 was prepared from 1-(4-chlorophenyl)cyclopentanecarboxylicacid andN-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 8.07 (d, 1H, J=8.4 Hz), 7.81 (s, 1H), 7.66 (t, 1H, J=7.6 Hz),7.36-7.33 (m, 2H), 7.30-7.27 (m, 2H), 6.90 (d, 1H, J=6.8 Hz), 6.60 (brs, 1H), 3.28 (dd, 2H, J=5.6, 12.0 Hz), 2.95 (d, 2H, J=11.6 Hz),2.55-2.49 (m, 4H), 2.33 (t, 2H, J=6.4 Hz), 2.00-1.61 (m, 14H), 1.26 (d,6H, J=6.8 Hz); ESMS m/e: 511.3 (M+H)⁺.

EXAMPLE 85

1-(4-CHLOROPHENYL)-N-(3-{4-[5-(ISOBUTYRYLAMINO)-2-METHYLPHENYL]-1-PIPERIDINYL}PROPYL)CYCLOHEXANECARBOXAMIDE:Example 85 was prepared from 1-(4-chlorophenyl)cyclohexanecarboxylicacid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 7.46 (d, 1H, J=1.6 Hz), 7.42-7.39 (m, 2H), 7.31-7.21 (m, 4H),7.08 (d, 1H, J=8.0 Hz), 6.78 (brs, 1H), 3.29 (dd, 2H, J=6.0, 12.0 Hz),2.93 (d, 2H, J=11.6 Hz), 2.65 (m, 1H), 2.50 (m, 1H), 2.34-2.30 (m, 4H),2.28 (s, 3H), 2.00-1.88 (m, 4H), 1.74-1.59 (m, 12H), 1.25 (d, 6H, J=6.8Hz); ESMS m/e: 538.3 (M+H)⁺.

EXAMPLE 86

1-(4-CHLOROPHENYL)-N-(3-{4-[5-(ISOBUTYRYLAMINO)-2-METHYLPHENYL]-1-PIPERIDINYL}PROPYL)CYCLOBUTANECARBOXAMIDE:Example 86 was prepared from 1-(4-chlorophenyl)cyclobutanecarboxylicacid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 7.46 (d, 1H, J=1.6 Hz), 7.34 (s, 4H), 7.28-7.23 (m, 2H), 7.10(d, 1H, J=8.4 Hz), 6.45 (brs, 1H), 3.31 (dd, 2H, J=5.6, 11.6 Hz), 2.95(d, 2H, J=11.6 Hz), 2.88-2.81 (m, 2H), 2.68 (m, 1H), 2.54-2.44 (m, 3H),2.33 (t, 2H, J=6.4 Hz), 2.29 (s, 3H), 2.11-1.90 (m, 4H), 1.76-1.63 (m,6H), 1.26 (d, 6H, J=7.2 Hz); ESMS m/e: 510.3 (M+H)⁺.

EXAMPLE 87

N-(3-{4-[3-(BUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-1-(4-FLUOROPHENYL)CYCLOHEXANECARBOXAMIDE: Example 87 was prepared from 1-(4-fluorophenyl)cyclohexanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to theprocedures described in Scheme 10: ¹H NMR (400 MHz, CDCl₃) δ 7.52 (s,1H), 7.44 (s, 1H), 7.41-7.37 (m, 2H), 7.29-7.23 (m, 2H), 7.02-6.97 (m,2H), 6.93 (d, 1H, J=206.8 Hz), 6.80 (br s, 1H), 3.29 (dd, 2H, J=5.6,11.6 Hz), 2.92 (d, 2H, J=11.6 Hz), 2.46 (m, 1H), 2.36-2.30 (m, 6H),1.96-1.30 (m, 18H), 1.01 (t, 3H, J=7.6 Hz), ESMS m/e: 508.3 (M+H)⁺.

EXAMPLE 88

2-(4-CHLOROPHENYL)-N-(3-{4-[6-(ISOBUTYRYLAMINO)-2-PYRIDINYL]-1-PIPERIDINYL}PROPYL)-2-METHYLPROPANAMIDE:Example 88 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acidand N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: ¹H NMR(400 MHz, CDCl₃) δ 8.08 (d, 1H, J=8.4 Hz), 7.82 (s, 1H), 7.67 (t, 1H,J=7.6 Hz), 7.33-7.27 (m, 4H), 6.88 (d, 1H, J=7.2 Hz), 6.57 (brs, 1H),3.33 (dd, 2H, J=6.0, 12.0 Hz), 2.94 (d, 2H, J=11.6 Hz), 2.58-2.53 (m,2H), 2.37 (t, 2H, J=6.4 Hz), 1.97 (t, 2H, J=11.2 Hz), 1.87 (d, 2H,J=13.2 Hz), 1.67-1.58 (m, 4H), 1.57 (s, 6H), 1.28 (d, 6H, J=7.2 Hz);ESMS m/e: 485.3 (M+H)⁺.

EXAMPLE 89

1-(4-CHLOROPHENYL)-N-(3-{4-[5-(ISOBUTYRYLAMINO)-2-METHYLPHENYL]-1-PIPERIDINYL}PROPYL)CYCLOPROPANECARBOXAMIDE:Example 89 was prepared from 1-(4-chlorophenyl)cyclopropanecarboxylicacid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]4-methylphenyl}-2-methylpropanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 7.40-7.32 (m, 7H), 7.08 (d, 1H, J=8.4 Hz), 5.70 (brs, 1H), 3.27(dd, 2H, J=6.4, 12.4 Hz), 2.88 (d, 2H, J=11.6 Hz), 2.64 (m, 1H), 2.53(m, 1H), 2.31 (t, 2H, J=6.8 Hz), 2.28 (s, 3H), 1.99 (dt, 2H, J=2.8, 11.2Hz), 1.67-1.60 (m, 8H), 1.27 (d, 6H, J=6.8 Hz), 1.03 (dd, 2H, J=4.0, 6.8Hz); ESMS m/e: 496.3 (M+H)⁺.

EXAMPLE 90

2-(4-CHLOROPHENYL)-N-(3-{4-[6-(ISOBUTYRYLAMINO)-2-PYRIDINYL]-1-PIPERIDINYL}PROPYL)PROPANAMIDE: Example 90 was prepared from2-(4-chlorophenyl)propanoic acid andN-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}2-methylpropanamideaccording procedures described in Scheme 10: ¹H NMR (400 MHz, CDCl₃) δ8.06 (d, 1H, J=8.0 Hz), 7.75 (s, 1H), 7.64 (t, 1H, J=7.6 Hz), 7.34-7.27(m, 4H), 7.22 (br s, 1H), 6.89 (d, 1H, J=7.6 Hz), 3.53 (q, 1H, J=7.2Hz), 3.36 (m, 1H), 3.29 (m, 1H), 3.05 (d, 1H, J=11.6 Hz), 2.95 (d, 1H,J=10.4 Hz), 2.58 (m, 1H), 2.45-2.40 (m, 3H), 2.02-1.63 (m, 8H), 1.50 (d,3H, J=7.2 Hz), 1.22 (dd, 6H, J=1.6, 6.8 Hz); ESMS m/e: 471.2 (M+H)⁺.

EXAMPLE 91

2-(4-CHLOROPHENYL)-N-(3-{4-[5-(ISOBUTYRYLAMINO)-2-METHYLPHENYL]-1-PIPERIDINYL}PROPYL)-2-METHYLPROPANAMIDE:Example 91 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acidandN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 7.41-7.27 (m, 7H), 7.09 (d, 1H, J=8.0 Hz), 6.59 (br s, 1H),3.34 (dd, 2H, J=6.4, 12.0 Hz), 2.93 (d, 2H, J=11.6 Hz), 2.64 (m, 1H),2.54 (m, 1H), 2.37 (t, 2H, J=6.4 Hz), 2.28 (s, 3H), 1.98 (t, 2H, J=12.4Hz), 1.71-1.64 (m, 4H), 1.59 (s, 6H), 1.61-1.55 (m, 2H), 1.28 (d, 6H,J=6.8 Hz); ESMS m/e: 498.3 (M+H)⁺.

EXAMPLE 92

1-(4-FLUOROPHENYL)-N-(3-{4-[5-(ISOBUTYRYLAMINO)-2-METHYLPHENYL]-1-PIPERIDINYL}PROPYL)CYCLOHEXANECARBOXAMIDE:Example 92 was prepared from 1-(4-fluorophenyl)cyclohexanecarboxylicacid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 7.46-7.43 (m, 3H), 7.26-7.22 (m, 2H), 7.10 (d, 1H, J=8.4 Hz),7.06-7.01 (m, 2H), 6.74 (br s, 1H), 3.31 (dd, 2H, J=6.0, 12.0 Hz), 2.96(d, 2H, J=11.6 Hz), 2.68 (m, 1H), 2.52 (m, 1H), 2.36-2.32 (m, 4H), 2.29(s, 3H), 2.03-1.90 (m, 4H), 1.74-1.61 (m, 12H), 1.27 (d, 6H, J=6.8 Hz);ESMS m/e: 522.3 (M+H)⁺.

EXAMPLE 93

1-(4-FLUOROPHENYL)-N-(3-{4-[5-(ISOBUTYRYLAMINO)-2-METHYLPHENYL]-1-PIPERIDINYL}PROPYL)CYCLOPENTANECARBOXAMIDE:Example 93 was prepared from 1-(4-fluorophenyl)cyclopentanecarboxylicacid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 7.43-7.37 (m, 3H), 7.29-7.27 (m, 2H), 7.09 (d, 1H, J=8.4 Hz),7.04-7.00 (m, 2H), 6.47 (br s, 1H), 3.29 (dd, 2H, J=5.6, 12.0 Hz), 2.94(d, 2H, J=12.0 Hz), 2.66 (m, 1H), 2.54-2.48 (m, 3H), 2.33-2.30 (m, 2H),2.29 (s, 3H), 2.03-1.95 (m, 4H), 1.84-1.60 (m, 10H), 1.26 (d, 6H, J=6.8Hz); ESMS m/e: 508.3 (M+H)⁺.

EXAMPLE 94

2-METHYL-N-[4-METHYL-3-(1-{3-[(TRIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL]PROPANAMIDE:Example 94 was prepared from triphenylacetic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 7.39 (dd, 1H, J=1.6, 8.0 Hz), 7.35-7.27 (m, 15H), 7.22-7.20 (m,2H), 7.09 (d, 1H, J=8.0 Hz), 6.25 (br s, 1H), 3.45 (dd, 2H, J=6.8, 12.4Hz), 2.90 (d, 2H, J=10.8 Hz), 2.63 (m, 1H), 2.52 (m, 1H), 2.33-2.29 (m,2H), 2.28 (s, 3H), 1.97 (t, 2H, J=10.0 Hz), 1.72-1.57 (m, 6H), 1.27 (d,6H, J=6.8 Hz); ESMS m/e: 588.3 (M+H)⁺.

EXAMPLE 95

N-(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-2-(4-CHLOROPHENYL)PROPANAMIDE: Example 95 was prepared from 2-(4-chlorophenyl) propanoicacid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl} acetamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 7.48 (s, 1H), 7.36 (s, 1H), 7.31-7.25 (m, 6H), 6.98-6.93 (m,2H), 3.51-3.48 (m, 1H), 3.35-3.31 (m, 2H), 3.03 (d, 1H, J=11.6 Hz), 2.93(d, 1H, J=11.2 Hz), 2.50 (m, 1H), 2.42-2.38 (m, 2H), 2.19 (s, 3H),2.05-1.96 (m, 2H), 1.90-1.80 (m, 2H), 1.70-1.59 (m, 4H), 1.51 (d, 3H,J=7.2 Hz); ESMS m/e: 442.2 (M+H)⁺.

EXAMPLE 96

N-(3-{4-[5-(ISOBUTYRYLAMINO)-2-METHYLPHENYL]-1-PIPERIDINYL}PROPYL)-2,2-DIPHENYLPROPANAMIDE:Example 96 was prepared from 2,2-diphenyl propanoic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]methyl phenyl}-2-methylpropanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 7.37-7.23 (m, 13H), 7.08 (d, 1H, J=8.8 Hz), 6.14 (t, 1H, J=5.6Hz), 3.37 (dd, 2H, J=6.4, 12.0 Hz), 2.90 (d, 2H, J=11.6 Hz), 2.63 (m,1H), 2.49 (m, 1H), 2.31 (t, 2H, J=6.8 Hz), 2.27 (s, 3H), 2.02 (s, 3H),1.99-1.94 (m, 2H), 1.71-1.59 (m, 6H), 1.25 (d, 6H, J=7.2 Hz); ESMS m/e:526.3 (M+H)⁺.

EXAMPLE 97

N-[3-(1-{3-[(2,2,2-TRIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL]BUTANAMIDE: Example 97 was prepared from tri phenylacetic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl} butanamide according tothe procedures described in Scheme 10: ¹H NMR (400 MHz, CDCl₃) δ 7.39(d, 2H, J=10.4 Hz), 7.34-7.21 (m, 17H), 6.90 (d, 1H, J=7.6 Hz), 6.31 (t,1H, J=5.2 Hz), 3.43 (dd, 2H, J=6.4, 12.4 Hz), 2.87 (d, 2H, J=12.0 Hz),2.41 (m, 1H), 2.31 (m, 4H), 1.92 (t, 2H, J=11.6 Hz), 1.79-1.66 (m, 6H),1.59-1.52 (m, 2H), 1.01 (t, 3H, J=7.2 Hz); ESMS m/e: 574.4 (M+H)⁺.

EXAMPLE 98

N-[3-(1-{3-[(2,2-DIPHENYLPROPANOYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL]BUTANAMIDE: Example 98 was prepared from 2,2-diphenylpropanoic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl] phenyl}butanamide according tothe procedures described in Scheme 10: ¹H NMR (400 MHz, CDCl₃) δ 7.43(s, 1H), 7.37-7.22 (m, 13H), 6.91 (d, 1H, J=7.2 Hz), 6.24 (br s, 1H),3.37 (dd, 2H, J=5.6, 11.6 Hz), 2.88 (d, 2H, J=11.6 Hz), 2.42 (m, 1H),2.32 (m, 4H), 2.01 (s, 3H), 1.93 (t, 2H, J=11.6 Hz), 1.81-1.52 (m, 8H),1.01 (t, 3H, J=6.8 Hz); ESMS m/e: 512.3 (M+H)⁺.

EXAMPLE 99

N-(3-{4-[3-(BUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-1-(4-CHLOROPHENYL)CYCLOHEXANECARBOXAMIDE: Example 99 was prepared from 1-(4-chlorophenylcyclohexanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to theprocedures described in Scheme 10: ¹H NMR (400 MHz, CDCl₃) δ 7.59 (s,1H), 7.52 (s, 1H), 7.38-7.35 (m, 2H), 7.30-7.22 (m, 4H), 6.93 (d, 1H,J=7.6 Hz), 6.87 (br s, 1H), 3.28 (dd, 2H, J=6.0, 12.0 Hz), 2.92 (d, 2H,J=11.6 Hz), 2.45 (m, 1H), 2.36-2.30 (m, 6H), 1.96-1.33 (m, 18H), 1.00(t, 3H, J=7.6 Hz); ESMS m/e: 524.3 (M+H)⁺.

EXAMPLE 100

2-(4-CHLOROPHENYL)-N-(3-{4-[5-(ISOBUTYRYLAMINO)-2-METHYLPHENYL]-1-PIPERIDINYL}PROPYL)PROPANAMIDE:Example 100 was prepared from 2-(4-chlorophenyl)propanoic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 7.56 (d, 1H, J=2.0 Hz), 7.34-7.28 (m, 5H), 7.21 (dd, 1H, J=2.0.8.0 Hz), 7.09 (d, 1H, J=8.0 Hz), 6.98 (brs, 1H), 3.55 (q, 1H, J=7.2 Hz),3.34 (m, 2H), 3.02 (d, 1H, J=11.6 Hz), 2.93 (d, 1H, J=11.6 Hz), 2.68 (m,1H), 2.51 (m, 1H), 2.39 (dt, 2H, J=6.8, 2.0 Hz), 2.29 (s, 3H), 2.04-1.97(m, 2H), 1.80-1.60 (m, 6H), 1.52 (d, 3H, J=7.2 Hz), 1.24 (dd, 6H, J=1.6,6.8 Hz); ESMS m/e: 484.3 (M+H)⁺.

EXAMPLE 101

N-(3-{4-[3-(BUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-1-(4-FLUOROPHENYL)CYCLOPENTANECARBOXAMIDE: Example 101 was prepared from1-(4-fluorophenyl) cyclopentanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to theprocedures described in Scheme 10: ¹H NMR (400 MHz, CDCl₃) δ 7.51 (s,1H), 7.37-7.24 (m, 6H), 7.02-6.95 (m, 2H), 6.51 (br s, 1H), 3.28 (dd,2H, J=5.6, 11.6 Hz), 2.93 (d, 2H, J=11.6 Hz), 2.53-2.48 (m, 3H),2.37-2.30 (m, 4H), 1.98-1.92 (m, 4H), 1.82-1.59 (m, 12H), 1.02 (t, 3H,J=7.6 Hz); ESMS m/e: 494.3 (M+H)⁺.

EXAMPLE 102

N-(3-{4-[3-(BUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-1-(4-CHLOROPHENYL)CYCLOPENTANECARBOXAMIDE: Example 102 was prepared from1-(4-chlorophenyl) cyclopentanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to theprocedures described in Scheme 10: ¹H NMR (400 MHz, CDCl₃) δ 7.51 (s,1H), 7.42 (s, 1H), 7.34-7.24 (m, 6H), 6.95 (d, 1H, J=7.6 Hz), 6.57 (brs, 1H), 3.28 (dd, 2H, J=5.6, 11.6 Hz), 2.92 (d, 2H, J=12.0 Hz),2.53-2.43 (m, 3H), 2.37-2.29 (m, 4H), 1.99-1.91 (m, 4H), 1.83-1.58 (m,12H), 1.02 (t, 3H, J=7.6 Hz); ESMS m/e: 510.3 (M+H)⁺.

EXAMPLE 103

N-(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-2,2-DIPHENYLPROPANAMIDE: Example 103 was prepared from 2,2-diphenyl propanoic acidand N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl} acetamide according tothe procedures described in Scheme 10: ¹H NMR (400 MHz, CDCl₃) δ7.37-7.23 (m, 14H), 6.93 (d, 1H, J=7.6 Hz), 6.20 (br s, 1H), 3.37 (dd,2H, J=6.4, 12.4 Hz), 2.89 (d, 2H, 7.2 Hz), 2.45 (m, 1H), 2.30 (m, 2H),2.18 (s, 3H), 2.01 (s, 3H), 1.94 (t, 2H, J=11.6 Hz), 1.76-1.53 (m, 6H);ESMS m/e: 484.2 (M+H)⁺.

EXAMPLE 104

N-{5-[1-(3-{[BIS(4-FLUOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]-2-FLUOROPHENYL}BUTANAMIDE:Example 104 was prepared from bis(4-fluoro phenyl)acetic acid andN-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}butanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 8.33-8.14 (m, 1H), 7.89-7.67 (br, 1H), 7.51-6.60 (m, 10H),4.98-4.79 (br, 1H), 4.75 (s, 1H), 3.46-3.29 (m, 2H), 3.29-3.08 (m, 2H),2.79-2.63 (m, 2H), 2.63-2.46 (m, 1H), 2.46-2.21 (m, 4H), 1.97-1.60 (m,8H), 1.01 (t, 3H, J=7.2 Hz); ESMS m/e: 552.3 (M+H)⁺.

EXAMPLE 105

N-(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-2,2,2-TRIPHENYLACETAMIDE: Example 105 was prepared from triphenylacetic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to theprocedures described in Scheme 10: ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.22(m, 19H), 6.91 (d, 1H, J=7.6 Hz), 6.30 (t, 1H, J=5.6 Hz), 3.43 (dd, 2H,J=6.4, 12.0 Hz), 2.87 (d, 2H, J=12.0 Hz), 2.42 (m, 1H), 2.30 (t, 2H,J=6.8 Hz), 2.17 (s, 3H), 1.93 (t, 2H, J=11.6 Hz), 1.74-1.66 (m, 4H),1.60-1.50 (m, 2H); ESMS m/e: 546.2 (M+H)⁺.

EXAMPLE 106

N-(3-{4-[3-(BUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-1-(4-CHLOROPHENYL)CYCLOBUTANECARBOXAMIDE: Example 106 was prepared from 1-(4-chlorophenyl)cyclobutanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to theprocedures described in Scheme 10: ¹H NMR (400 MHz, CDCl₃) δ 7.53 (s,2H), 7.32-7.23 (m, 6H), 6.95 (d, 1H, J=7.6 Hz), 6.53 (br s, 1H), 3.29(dd, 2H, J=6.0, 12.4 Hz), 2.93 (d, 2H, J=10.8 Hz), 2.86-2.79 (m, 2H),2.48-2.41 (m, 3H), 2.37-2.30 (m, 4H), 2.07 (m, 1H), 1.98-1.61 (m, 11H),1.01 (t, 3H, J=7.6 Hz); ESMS m/e: 496.3 (M+H)⁺.

EXAMPLE 107

N-(3-{4-[3-(BUTYRYLAMINO)-4-FLUOROPHENYL]-1-PIPERIDINYL}PROPYL)-1-(4-FLUOROPHENYL)CYCLOPENTANECARBOXAMIDE:Example 107 was prepared from 1-(4-fluorophenyl)cyclopentanecarboxylicacid and N-{5-[1-(3-aminopropyl-4-piperidinyl]-2-fluorophenyl}butanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 8.30-8.13 (m, 1H), 8.09-7.95 (br, 1H), 7.47-7.26 (m, 3H),7.08-6.87 (m, 3H), 6.75-6.54 (br, 1H), 3.30-3.07 (m, 4H), 2.59-2.44 (m,3H), 2.44-2.33 (m, 2H), 2.33-2.19 (m, 2H), 1.99-1.69 (m, 16H), 1.02 (t,3H, J=7.2 Hz); ESMS m/e: 512.3 (M+H)⁺.

EXAMPLE 108

N-{5-[1-(3-{[BIS(4-CHLOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]-2-FLUOROPHENYL}BUTANAMIDE:Example 108 was prepared from bis(4-chlorophenyl) acetic acid andN-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}butan amideaccording to the procedures described in Scheme 10: ESMS m/e: 584.2(M+H)⁺.

EXAMPLE 109

N-{5-[1-(3-{[BIS(4-METHYLPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]-2-FLUOROPHENYL}BUTANAMIDE:Example 10 prepared from bis(4-methylphenyl)acetic acid andN-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl} butanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 8.30-8.13 (m, 1H), 8.08-7.92 (br, 1H), 7.43-6.89 (m, 9H),6.76-6.61 (br, 1H), 4.98-4.79 (br, 1H), 4.70 (s, 1H), 3.39-3.16 (m, 4H),2.83-2.63 (m, 2H), 2.63-2.47 (m, 1H), 2.45-2.12 (m, 4H), 2.27 (s, 6H),2.02-1.64 (m, 8H), 1.02 (t, 3H, J=7.2 Hz); ESMS m/e: 544.4 (M+H)⁺.

EXAMPLE 110

N-{5-[1-(3-{[2-(4-CHLOROPHENYL)-2-METHYLPROPANOYL]AMINO}PROPYL)-4-PIPERIDINYL]-2-FLUOROPHENYL}BUTANAMIDE:Example 110 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acidand N{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}butanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 8.31-8.12 (m, 1H), 7.44-7.15 (m, 5H), 7.12-6.94 (m, 1H),6.75-6.61 (br, 1H), 6.61-6.46 (br, 1H), 3.35-3.12 (m, 4H), 2.70-2.47 (m,3H), 2.46-2.35 (m, 2H), 2.35-2.21 (m, 2H), 1.92-1.67 (m, 8H), 1.54 (s,6H), 1.02 (t, 3H, J=7.2 Hz); ESMS m/e: 502.3 (M+H)⁺.

EXAMPLE 111

N-{3-[1-(3-{[2,2-BIS(4-METHYLPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]PHENYL}CYCLOPROPANECARBOXAMIDE: Example 111 was prepared frombis(4-methylphenyl)acetic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 8.24-8.04 (br, 1H), 8.04-7.95 (br, 1H), 7.59-6.92 (m, 10H),6.90-6.76 (m, 1H), 4.98-4.82 (br, 1H), 4.72 (s, 1H), 3.42-3.25 (m, 2H),3.25-3.08 (m, 2H), 2.75-2.56 (m, 2H), 2.56-2.40 (m, 1H), 2.35-2.17 (m,2H), 2.26 (s, 6H), 1.99-1.68 (m, 6H), 1.57-1.44 (m, 1H), 1.12-0.99 (m,2H), 0.87-0.70 (m, 2H); ESMS m/e: 524.3 (M+H)⁺; Anal. Calc. for (HClsalt) C₃₄H₄₂ClF₂N₃O₂.0.29CHCl₃: C, 69.23; H, 7.16; N, 7.06. Found: C,68.96; H, 7.35; N, 7.31.

EXAMPLE 112

1-(4-CHLOROPHENYL)-N-[3-(4-{3-[(CYCLOPROPYLCARBONYL)AMINO]PHENYL}1-PIPERIDINYL)PROPYL]CYCLOPENTANECARBOXAMIDE:Example 112 was prepared from 1-(4-chlorophenyl)cyclopentanecarboxylicacid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 8.03-7.87 (br, 1H), 7.56-7.02 (m, 8H), 6.91-6.65 (br, 1H),3.30-3.05 (m, 4H), 2.62-2.38 (m, 3H), 2.38-2.21 (m, 2H), 1.98-1.51 (m,15H), 1.14-1.01 (m, 2H), 0.93-0.70 (m, 2H); ESMS m/e: 508.2 (M+H)⁺.

EXAMPLE 113

N-{3-[1-(3-{[2,2-BIS(4-CHLOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]PHENYL}CYCLOPROPANECARBOXAMIDE: Example 113 was prepared frombis(4-chlorophenyl)acetic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 7.84-7.80 (br, 1H), 7.80-7.69 (br, 1H), 7.64-7.46 (br, 1H),7.40-6.90 (m, 9H), 6.85-8.66 (m, 1H), 4.94-4.74 (br, 1H), 4.69 (s, 1H),3.41-3.25 (m, 2H), 3.25-3.07 (m, 2H), 2.77-2.61 (m, 2H), 2.61-2.45 (m,1H), 2.45-2.17 (m, 2H), 1.99-1.63 (m, 6H), 1.61-1.39 (m, 1H), 1.14-0.94(m, 2H), 0.92-0.70 (m, 2H); ESMS m/e: 564.2 (M+H)⁺.

EXAMPLE 114

N-[3-(1-{3-[(2,2,2-TRIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL]CYCLOPROPANECARBOXAMIDE: Example 114 was prepared from triphenylaceticacid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenylcyclopropanecarboxamide according to the procedures described inScheme 10: ESMS m/e: 572.3 (M+H)⁺.

EXAMPLE 115

N-{3-[1-(3-{[2-(4-CHLOROPHENYL)-2-METHYLPROPANOYL]AMINO}PROPYL)-4-PIPERIDINYL]PHENYL}CYCLOPROPANECARBOXAMIDE:Example 115 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acidand N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide according to theprocedures described in Scheme 10: ¹H NMR (400 MHz, CDCl₃)

7.94-7.81 (br, 1H), 7.53-7.40 (br, 1H) (m, 6H), 6.82 (d, 1H, J=7.2 Hz),6.68-6.49 (br, 1H), 3.33-3.19 (m, 2H), 3.19-3.06 (m, 2H), 2.63-2.39 (m,3H), 2.31-2.09 (m, 2H), 1.89-1.62 (m, 7H), 1.54 (s, 6H), 1.13-0.98 (m,2H), 0.90-0.72 (m, 2H); ESMS m/e: 482.2 (M+H)⁺.

EXAMPLE 116

N-{3-[1-(3-{[2-(4-CHLOROPHENYL)PROPANOYL]AMINO}PROPYL)-4-PIPERIDINYL]PHENYL}CYCLOPROPANECARBOXAMIDE: Example 116 was prepared from2-(4-chlorophenyl)propanoic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃)

8.15-7.95 (br, 1H), 7.63-7.44 (br, 1H), 7.39-7.12 (m, 6.8 Hz), 3.74-3.55(m, 1H), 3.45-3.22 (m, 2H), 3.22-3.12 (m, 1H), 3.12-3.00 (m, 1H),2.66-2.40 (m, 3H), 2.29-2.09 (m, 2H), 1.92-1.63 (m, 6H), 1.64-1.51 (m,1H), 1.47 (d, 3H, J=6.8 Hz), 1.18-0.98 (m, 2H), 0.91-0.74 (m, 2H); ESMSm/e: 468.2 (M+H)⁺; Anal. Calc. for (HCl salt) C₂₇H₃₅Cl₂N₃O₂.0.28CHCl₃:C, 60.91; H, 6.61; N, 7.81; Found: C, 60.66; H, 6.90; N, 8.19.

EXAMPLE 117

N-[3-(4-{3-[(CYCLOPROPYLCARBONYL)AMINO]PHENYL}-1-PIPERIDINYL)PROPYL]-1-(2,4-DICHLOROPHENYL)CYCLOPROPANECARBOXAMIDE: Example 117 wasprepared from 1-(2,4-dichlorophenyl)cyclopropanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropane carboxamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 8.00-7.82 (br, 1H), 7.52-7.04 (m, 6H), 6.86 (d, 1H, J=7.2 Hz),5.92-5.73 (br, 1H), 3.35-3.12 (m, 4H), 2.74-2.58 (m, 2H), 2.58-2.42 (m,1H), 2.40-2.20 (m, 2H), 2.01-1.61 (m, 7H), 1.15-0.90 (m, 6H), 0.89-0.71(m, 2H); ESMS m/e: 514.2 (M+H)⁺.

EXAMPLE 118

1-(4-CHLOROPHENYL-N-[3-(4-{3-[CYCLOPROPYLCARBONYL)AMINO]PHENYL}-1-PIPERIDINYL)PROPYL]CYCLOPROPANECARBOXAMIDE:Example 118 was prepared from 1-(4-chlorophenyl)cyclopropanecarboxylicacid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃)

8.12-7.88 (br, 1H), 7.48-7.14 (m, 7H), J=7.2 Hz), 5.83-5.66 (br, 1H),3.29-3.09 (m, 4H), 2.66-2.53 (m, 2H), 2.53-2.40 (m, 1H), 2.37-2.17 (m,2H), 1.95-1.53 (m, 7H), 1.14-0.91 (m, 6H), 0.89-0.71 (m, 2H); ESMS m/e:480.2 (M+H)⁺; Anal. Calc. (HCl salt) C₂₈H₃₅Cl₂N₃O₂.0.38CHCl₃: C, 60.64;H, 6.34; N, 7.47. Found: C, 60.38; H, 6.57; N, 7.80.

EXAMPLE 119

1-(2-CHLORO-4-FLUOROPHENYL)-N-[3-(4-{3-[(CYCLOPROPYLCARBONYL)AMINO]PHENYL}-1-PIPERIDINYL)PROPYL]CYCLOPENTANECARBOXAMIDE: Example 119 wasprepared from 1-(2-chloro-4-fluorophenyl)cyclopentanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropane carboxamideaccording to the procedures described in Scheme 10: ESMS m/e: 526.2(M+H)⁺.

EXAMPLE 120

N-{3-[1-(3-{[2,2-BIS(4-FLUOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]PHENYL}CYCLOPROPANECARBOXAMIDE: Example 120 was prepared frombis(4-fluorophenyl)acetic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 7.64-7.55 (s, 1H), 7.55-7.47 (s, 1H), 7.47-7.37 (br, 1H),7.36-7.17 (m, 6H), 7.05-6.95 (m, 4H), 6.95-6.87 (br, 1H), 4.81 (s, 1H),3.47-3.35 (m, 2H), 3.07-2.94 (m, 2H), 2.58-2.41 (m, 3H), 2.15-1.99 (m,2H), 1.90-1.79 (m, 2H), 1.79-1.60 (m, 4H), 1.59-1.44 (m, 1H), 1.13-0.99(m, 2H), 0.90-0.75 (m, 2H); ESMS m/e: 532.2 (M+H)⁺.

EXAMPLE 121

N-[3-(4-{3-[(CYCLOPROPYLCARBONYL)AMINO]PHENYL}-1-PIPERIDINYL)PROPYL]-1-(4-FLUOROPHENYL)CYCLOPENTANECARBOXAMIDE: Example 121 wasprepared from 1-(4-fluorophenyl)cyclopentanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl] phenyl}cyclopropanecarboxamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 7.94-7.72 (br, 1H), 7.48-6.84 (m, 7H), 6.75 (d, 1H, J=7.2 Hz),6.68-6.55 (br, 1H), 3.25-3.05 (m, 4H), 2.58-2.39 (m, 3H), 2.33-2.15 (m,2H), 2.00-1.48 (m, 15H), 1.13-1.01 (m, 2H), 0.93-0.73 (m, 2H); ESMS m/e:492.3 (M+H)⁺.

EXAMPLE 122

N-[3-(1-{3-[(2,2-DIPHENYLBUTANOYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL]CYCLOPROPANECARBOXAMIDE: Example 122 was prepared from2,2-diphenylbutanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described inScheme 10: ¹H NMR (400 MHz, CDCl₃) δ 7.89-7.74 (br, 1H), 7.48-7.05 (m,13H), 6.89-6.74 (d, 1H, J=7.2 Hz), 6.46-6.25 (br, 1H), 3.30-3.15 (m,2H), 3.15-3.01 (m, 2H), 2.38-2.25 (m, 3H), 2.25-2.09 (m, 2H), 1.99-1.78(m, 3H), 1.78-1.60 (m, 5H), 1.60-1.47 (m, 1H), 1.12-1.01 (m, 2H),0.90-0.71 (m, 2H), 0.75 (t, 3H, J=7.2 Hz); ESMS m/e: 524.3 (M+H)⁺.

EXAMPLE 123

N-[3-(1-{3-[(2,2-DIPHENYLPROPANOYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL]CYCLOPROPANECARBOXAMIDE: Example 123 was prepared from2,2-diphenylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described inScheme 10: ESMS m/e: 510.3 (M+H)⁺.

EXAMPLE 124

N-{3-[1-(3-{[DIFLUORO(PHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]-4-METHYLPHENYL}-2-METHYLPROPANAMIDE:Example 124 was prepared from 2,2-difluoro-2-phenylacetic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]methylphenyl}-2-methyl propanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 8.00 (s, 2H), 7.68-7.63 (m, 3H), 7.49-7.39 (m, 3H), 7.23 (d,1H, J=1.8 Hz), 7.07 (d, 1H, J=8.3 Hz), 3.45 (q, 2H, J=4.9 Hz), 3.11 (d,2H, J=10.2 Hz), 2.76-2.66 (m, 1H), 2.56 (t, 2H, J=5.0 Hz), 2.44 (septet,1H, J=6.9 Hz), 2.28 (s, 3H), 2.13-2.05 (m, 2H), 1.82-1.71 (m, 6H), 1.15(d, 6H, J=6.9 Hz); ESMS m/e: 472.4 (M+H)⁺.

EXAMPLE 125

N-{3-[1-(3{[DIFLUORO(PHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]PHENYL}2-METHYLPROPANAMIDE: Example 125 was prepared from2,2-difluoro-2-phenylacetic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 8.01 (s, 1H), 7.71 (s, 1H), 7.65-7.62 (m, 2H), 7.50 (s, 1H),7.47-7.40 (m, 3H), 7.35 (d, 1H, J=7.6 Hz), 7.22 (t, 1H, J=7.2 Hz), 6.95(d, 1H, J=7.8 Hz), 3.45 (q, 2H, J=5.3 Hz), 3.10 (d, 2H, J=10.9 Hz),2.59-2.45 (m, 4H), 2.11-2.02 (m, 2H), 1.89-1.71 (m, 6H), 1.20 (d, 6H,J=6.9 Hz); ESMS m/e: 458.4 (M+H)⁺.

EXAMPLE 126

N-[3-(1-{3-[(DIPHENYLACETYL)(ETHYL)AMINO]PROPYL}4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:Example 126 was prepared from diphenylacetyl chloride andN-(3-{1-[3-(ethylamino)propyl]-4-piperidinyl}phenyl)-2-methylpropanamideaccording to the procedures described in Scheme 8: ¹H NMR (400 MHz,CDCl₃) δ 7.33-7.21 (m, 13H), 6.94 (m, 2H), 4.88 (s, 1H), 3.39 (m, 4H),2.93 (d, 2H, J=10.9 Hz), 2.52-2.36 (m, 7H), 1.97 (t, 2H, J=10.9 Hz),1.83-1.58 (m, 6H), 1.24 (d, 6H, J=7.6 Hz); ESMS m/e: 526.4 (M+H)⁺.

EXAMPLE 127

2-(4-CHLOROPHENYL)-N-(3-{4-[2-FLUORO-5-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-2-METHYLPROPANAMIDE:Example 127 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acidandN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 7.95 (s, 1H), 7.73 (s, 1H), 7.68 (s, 1H), 7.43-7.38 (m, 1H),7.37-7.26 (m, 3H), 6.93-6.83 (m, 2H), 3.96-3.61 (m, 1H), 3.26-3.02 (m,4H), 2.69-2.59 (m, 1H), 2.51-2.40 (m, 2H), 1.90-1.71 (m, 4H), 1.63-1.47(m, 4H), 1.18 (d, 6H, J=6.9 Hz), 1.15 (s, 6H); ESMS m/e: 502.1 (M+H)⁺.

EXAMPLE 128

1-(4-CHLOROPHENYL)-N-(3-{4-[2-FLUORO-5-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)CYCLOPENTANECARBOXAMIDE:Example 128 was prepared from 1-(4-chlorophenyl)cyclopentanecarboxylicacid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]fluorophenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 7.45 (s, 1H), 7.42-7.38 (m, 1H), 7.27-7.17 (m, 4H), 7.12-7.09(m, 1H), 6.87 (t, 1H, J=8.6 Hz), 6.49 (t, 1H, J=5.4 Hz), 3.19 (q, 2H,J=5.8 Hz), 2.85-2.79 (m, 2H), 2.73-2.64 (m, 1H), 2.50-2.35 (m, 3H), 2.23(t, 2H, J=6.6 Hz), 1.92-1.85 (m, 4H), 1.75-1.48 (m, 10H), 1.17 (d, 6H,J=6.7 Hz); ESMS m/e: 528.2 (M+H)⁺.

EXAMPLE 129

N-(3-{4-[2-FLUORO-5-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-1-(4-FLUOROPHENYL)CYCLOPENTANECARBOXAMIDE:Example 129 was prepared from 1-(4-fluorophenyl)cyclopentanecarboxylicacid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 7.53 (s, 1H), 7.42-7.38 (m, 1H), 7.31-7.20 (m, 2H), 6.94-6.83(m, 4H), 6.46-6.40 (m, 1H), 3.19 (q, 2H, J=5.6 Hz), 2.85-2.79 (m, 2H),2.73-2.64 (m, 1H), 2.49-2.38 (m, 3H), 2.22 (t, 2H, J=6.4 Hz), 1.94-1.84(m, 5H), 1.75-1.47 (m, 9H), 1.17 (d, 6H, J=6.8 Hz); ESMS m/e: 512.3(M+H)⁺.

EXAMPLE 130

1-(4-CHLOROPHENYL)-N-(3-{4-[2-FLUORO-5-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)CYCLOHEXANECARBOXAMIDE:Example 130 was prepared from 1-(4-chlorophenyl)cyclohexanecarboxylicacid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 7.45-7.40 (m, 1H), 7.34-7.29 (m, 3H), 7.24-7.16 (m, 3H), 6.88(t, 1H, J=8.7 Hz), 6.77-6.72 (m, 1H), 3.21 (q, 2H, J=5.6 Hz), 2.87-2.81(m, 2H), 2.74-2.65 (m, 1H), 2.44 (septet, 1H, J=6.7 Hz), 2.28-2.21 (m,4H), 1.92-1.76 (m, 4H), 1.69-1.69 (m, 4H), 1.56-1.47 (m, 8H), 1.18 (d,6H, J=6.7 Hz); ESMS m/e: 542.2 (M+H)⁺; Anal. Calc. forC₃₁H₄₁ClFN₃O₂.HCl.0.20CHCl₃: C, 62.20; H, 7.06; N, 6.97. Found: C,62.24; H, 7.03; N, 6.79.

EXAMPLE 131

N-(3-{4-[2-FLUORO-5-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-1-(4-FLUOROPHENYL)CYCLOHEXANECARBOXAMIDE:Example 131 was prepared from 1-(4-fluorophenyl)cyclohexanecarboxylicacid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 7.49 (s, 1H), 7.43 (dd, 1H, J=6.9, 2.5 Hz), 7.36-7.31 (m, 2H),7.23-7.17 (m, 1H), 6.93 (t, 2H, J=8.4 Hz), 6.87 (t, 1H, J=8.9 Hz),6.73-6.68 (m, 1H), 3.21 (q, 2H, J=5.7 Hz), 2.87-2.80 (m, 2H), 2.73-2.65(m, 1H), 2.45 (septet, 1H, J=6.7 Hz), 2.30-2.21 (m, 4H), 1.9-1.77 (m,5H), 1.70-1.63 (m, 3H), 1.56-1.45 (m, 8H), 1.17 (d, 6H, J=6.7 Hz); ESMSm/e: 526.3 (M+H)⁺.

EXAMPLE 132

N-{3-[1-(3-{[BIS(4-METHYLPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]-4-FLUOROPHENYL}-2-METHYLPROPANAMIDE:Example 132 was prepared from bis(4-methylphenyl)acetic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 7.72 (s, 1H), 7.36-7.31 (m, 1H), 7.28-7.21 (m, 1H), 7.12-7.07(m, 3H), 7.03-6.99 (m, 5H), 6.86-6.80 (m, 1H), 6.79-6.75 (m, 1H), 4.74(s, 1H), 3.33-3.25 (m, 2H), 2.85-2.77 (m, 2H), 2.72-2.62 (m, 1H), 2.40(septet, 1H, J=6.7 Hz), 2.28 (t, 2H, J=6.6 Hz), 2.21 (m, 6H), 1.94-1.84(m, 2H), 1.65-1.52 (m, 6H), 1.71 (d, 6H, J=6.6 Hz); ESMS m/e: 544.3(M+H)⁺; Anal. Calc. for C₃₄H₄₂FN₃O₂.HCl.0.10CHCl₃: C, 70.17; H, 7.35; N,7.10. Found: C, 70.35; H, 6.99; N, 7.10.

EXAMPLE 133

1-(2-CHLORO-4-FLUOROPHENYL)-N-(3-{4-[2-FLUORO-5-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)CYCLO HEXANECARBOXAMIDE: Example 133 wasprepared from 1-(2-chloro-4-fluorophenyl)cyclohexanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 7.59 (dd, 1H, J=6.4, 8.6 Hz), 7.44-7.38 (m, 2H), 7.35-7.30 (m,1H), 7.13 (dd, 1H, J=8.5, 3.0 Hz), 7.00-6.91 (m, 2H), 6.05-5.99 (m, 1H),3.30 (q, 2H, J=5.7 Hz), 2.92-2.86 (m, 2H), 2.80-2.71 (m, 1H), 2.52(septet, 1H, J=6.7 Hz), 2.34 (t, 2H, J=5.7 Hz), 2.30-2.24 (m, 3H),2.13-2.05 (m, 2H), 2.00-1.92 (m, 2H), 1.86-1.69 (m, 4H), 1.66-1.43 (m,7H), 1.71 (d, 6H, J=6.7 Hz); ESMS m/e: 560.1 (M+H)⁺.

EXAMPLE 134

1-(2-CHLORO-4-FLUOROPHENYL)-N-(3-{4-[5-(ISOBUTYRYLAMINO)-2-METHYLPHENYL]-1-PIPERIDINYL}PROPYL)CYCLOHEXANECARBOXAMIDE:Example 134 was prepared from 1-(2-chloro-4-fluorophenyl)cyclohexanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 7.55 (dd, 1H, J=8.9, 6.3 Hz), 7.32 (s, 1H), 7.23-7.18 (m, 2H),7.06 (dd, 1H, J=8.5, 3.0 Hz), 7.01-6.92 (m, 2H), 5.99-5.93 (m, 1H), 3.24(q, 2H, J=5.9 Hz), 2.85-2.79 (m, 3H), 2.59-2.50 (m, 1H), 2.44 (septet,1H, J=7.0 Hz), 2.41-2.37 (br, 1H), 2.26 (t, 2H, J=5.7 Hz), 2.19 (s, 3H),2.07-2.01 (m, 2H), 1.81-1.69 (m, 4H), 1.61-1.37 (m, 10H), 1.17 (d, 6H,J=7.0 Hz); ESMS m/e: 556.1 (M+H)⁺.

EXAMPLE 135

1-(2-CHLORO-4-FLUOROPHENYL)-N-(3-{4-[5-(ISOBUTYRYLAMINO)-2-METHYLPHENYL]-1-PIPERIDINYL}PROPYL)CYCLOPENTANECARBOXAMIDE: Example 135 wasprepared from 1-(2-chloro-4-fluorophenyl)cyclopentanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according tothe procedures described in Scheme 9: ¹H NMR (400 MHz, CDCl₃) δ 7.56(dd, 1H, J=8.7, 6.3 Hz), 7.32 (s, 1H), 7.22-7.15 (m, 2H), 7.06 (dd, 1H,J=8.7, 3.0 Hz), 7.05-6.95 (m, 2H), 5.90-5.84 (m, 1H), 3.21 (q, 2H, J=5.7Hz), 2.87-2.80 (m, 2H), 2.59-2.49 (m, 1H), 2.44 (septet, 1H, J=6.5 Hz),2.41-2.40 (m, 2H), 2.26 (t, 2H, J=5.7 Hz), 2.19 (s, 3H), 2.04-1.96 (m,2H), 1.93-1.85 (m, 2H), 1.82-1.71 (m, 3H), 1.64-1.48 (m, 7H), 1.17 (d,6H, J=6.5 Hz); ESMS m/e: 542.2 (M+H)⁺.

EXAMPLE 136

N-{3-[1-(3-{[DIFLUORO(PHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]-4-FLUOROPHENYL}-2-METHYLPROPANAMIDE:Example 136 was prepared from 2,2-difluoro-2-phenylacetic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]4-fluorophenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 9.11 (s, 1H), 7.61-7.56 (m, 2H), 7.41-7.34 (m, 4H), 7.21-7.17(m, 1H), 7.14 (s, 1H), 6.88 (t, 1H, J=9.5 Hz), 3.39 (q, 2H, J=5.7 Hz),3.08-3.01 (m, 2H), 2.84-2.74 (m, 1H), 2.50 (t, 2H, J=5.1 Hz), 2.38(septet, 1H, J=7.2 Hz), 2.08-1.99 (m, 2H), 1.81-1.73 (m, 4H), 1.72-1.64(m, 2H), 1.17 (d, 6H, J=7.2 Hz); ESMS m/e: 476.2 (M+H)⁺.

EXAMPLE 137

1-(2-CHLORO-4-FLUOROPHENYL)-N-(3-{4-[2-FLUORO-5-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)CYCLOPENTANECARBOXAMIDE: Example 137 wasprepared from 1-(2-chloro-4-fluorophenyl)cyclopentanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ESMS m/e: 546.1(M+H)⁺.

EXAMPLE 138

1-(2-CHLORO-4-FLUOROPHENYL)-N-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)CYCLOHEXANECARBOXAMIDE:Example 138 was prepared from1-(2-chloro-4-fluorophenyl)cyclohexanecarboxylic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamideaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 7.52-7.46 (m, 1H), 7.45-7.43 (m, 1H), 7.30 (s, 1H), 7.22 (s,1H), 7.17 (t, 1H, J=7.9 Hz), 7.07-7.01 (m, 2H), 6.89-6.84 (m, 1H),5.99-5.94 (m, 1H), 3.21 (q, 2H, J=5.7 Hz), 2.87-2.80 (m, 2H), 2.59-2.49(m, 1H), 2.44 (septet, 1H, J=6.5 Hz), 2.41-2.40 (m, 2H), 2.26 (t, 2H,J=5.7 Hz), 2.04-1.96 (m, 2H), 1.93-1.85 (m, 2H), 1.82-1.71 (m, 4H),1.64-1.50 (m, 8H), 1.17 (d, 6H, J=6.5 Hz); ESMS m/e: 542.1 (M+H)⁺.

EXAMPLE 139

N-{3-[4-(3-{[(DIMETHYLAMINO)CARBONYL]AMINO}PHENYL)-1-PIPERIDINYL]PROPYL}-2,2-BIS(4-FLUOROPHENYL)ACETAMIDE:Example 139 was prepared from bis(4-fluoro phenyl)acetic acid andN′-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-N,N-dimethylureaaccording to the procedures described in Scheme 9: ESMS m/e: 535.4(M+H)⁺.

EXAMPLE 140

Benzyl3-(1-{3-[(Diphenylacetyl)Amino]Propyl}-4-Piperidinyl)Phenylcarbamate:Example 140 was prepared from diphenylacetyl chloride and benzyl3-[1-(3-aminopropyl)-4-piperidinyl]phenyl carbamate according to theprocedures described in Scheme 8: ESMS m/e: 562.5 (M+H)⁺.

EXAMPLE 141

Benzyl3-[1-(3-{[bis(4-fluorophenyl)acetyl]amino}propyl)-4-piperidinyl]phenylcarbamate:Example 141 was prepared from bis(4-fluorophenyl)acetic acid and benzyl3-[1-(3-amino propyl)-4-piperidinyl]phenylcarbamate according to theprocedures described in Scheme 9: ESMS m/e: 598.5 (M+H)⁺.

EXAMPLE 142

Isopropyl3-[1-(3-{[2-(4-Chlorophenyl)-2-Methylpropanoyl]Amino}Propyl)-4-Piperidinyl]Phenylcarbamate: Example 142 was prepared from2-(4-chlorophenyl)-2-methylpropanoic acid and isopropyl3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate according to theprocedures described in Scheme 9: ¹H NMR (400 MHz, CDCl₃) δ 7.29-7.22(m, 3H), 7.20-7.11 (m, 3H), 7.09-7.06 (m, 1H), 6.79 (d, 1H, J=7.6 Hz),6.61 (s, 1H), 6.60-6.50 (m, 1H), 4.94 (septet, 1H, J=6.7 Hz), 4.05 (q,1H, J=6.8 Hz), 3.24 (q, 2H, J=5.9 Hz), 2.86-2.79 (m, 2H), 2.36 (tt, 1H,J=11.9, 3.2 Hz), 2.27 (t, 2H, J=6.3 Hz), 1.85 (t, 2H, J=11.9 Hz),1.72-1.66 (m, 2H), 1.60-1.52 (m, 3H), 1.48 (s, 6H), 1.23 (d, 6H, J=6.7Hz); ESMS m/e: 500.2 (M+H)⁺.

EXAMPLE 143

Isopropyl3-[1-(3-{[bis(4-chlorophenyl)acetyl]amino}propyl)-4-piperidinyl]phenylcarbamate:Example 143 was prepared from bis(4-chlorophenyl)acetic acid andisopropyl 3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate accordingto the procedures described in Scheme 9: ¹H NMR (400 MHz, CDCl₃) δ 7.46(s, 1H), 7.37 (s, 1H), 7.23-7.10 (m, 9H), 7.00 (d, 1H, J=7.9 Hz), 6.80(d, 1H, J=7.4 Hz), 6.60 (s, 1H), 4.88 (septet, 1H, J=6.2 Hz), 4.68 (s,1H), 4.05 (q, 1H, J=7.3 Hz), 3.32 (q, 2H, J=5.9 Hz), 2.90-2.83 (m, 2H),2.44-2.32 (m, 3H), 1.94-1.86 (m, 2H), 1.78-1.70 (m, 2H), 1.60 (quintet,2H, J=6.4 Hz), 1.56-1.43 (m, 1H), 1.22 (d, 6H, J=6.2 Hz); ESMS m/e:582.2 (M+H)⁺.

EXAMPLE 144

Isopropyl 3-(1-{3-[(Diphenylacetyl)Amino]Propyl}-4-Piperidinyl)Phenylcarbamate: Example 144 was prepared from diphenylacetyl chlorideand isopropyl 3-[1-(3-aminopropyl)-4-piperidinyl]phenyl carbamateaccording to the procedures described in Scheme 9: ¹H NMR (400 MHz,CDCl₃) δ 7.25-7.12 (m, 12H), 7.09-7.06 (m, 1H), 7.00-6.94 (m, 1H), 6.79(d, 1H, J=7.6 Hz), 6.60(s, 1H), 4.92 (septet, 1H, J=6.2 Hz), 4.79 (s,1H), 4.04 (q, 1H, J=6.4 Hz), 3.30 (q, 2H, J=5.8 Hz) 2.91-2.83 (m, 2H),2.42-2.30 (m, 3H), 1.91 (t, 2H, J=11.4 Hz), 1.74-1.67 (m, 2H), 1.65-1.51(m, 3H), 1.21 (d, 6H, J=6.2 Hz); ESMS m/e: 514.2 (M+H)⁺.

EXAMPLE 145

ISOPROPYL3-[1-(3-{[BIS(4-METHYLPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]PHENYLCARBAMATE:Example 145 was prepared from bis(4-methylphenyl)acetic acid andisopropyl 3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate accordingto the procedures described in Scheme 9: ¹H NMR (400 MHz, CDCl₃) δ 7.24(s, 1H), 7.18-7.06 (m, 4H), 7.06-7.00 (m, 6H), 6.82-6.78 (m, 2H), 6.62(s, 1H), 4.92 (septet, 1H, J=6.7 Hz), 4.72 (s, 1H), 4.04 (q, 1H, J=6.8Hz), 3.32-3.26 (m, 2H), 2.88-2.81 (m, 2H), 2.41-2.27 (m, 3H), 2.21 (s,6H), 1.92-1.83 (m, 2H), 1.74-1.66 (m, 2H), 1.62-1.46 (m, 3H), 1.21 (d,6H, J=6.7 Hz); ESMS m/e: 542.3 (M+H)⁺.

EXAMPLE 146

ISOPROPYL3-[1-(3-{[BIS(4-FLUOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]PHENYLCARBAMATE:Example 146 was prepared from bis(4-fluoro phenyl)acetic acid andisopropyl 3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate accordingto the procedures described in Scheme 9: ¹H NMR (400 MHz, CDCl₃) δ7.43(s, 2H), 7.30-7.19 (m, 4H), 7.11-7.07 (m, 1H), 7.01-6.96 (m, 5H),6.88 (d, 1H, J=7.7 Hz), 6.69 (s, 1H), 4.97 (septet, 1H, J=6.3 Hz), 4.79(s, 1H), 4.11 (q, 1H, J=6.8 Hz), 3.39 (q, 2H, J=5.6 Hz), 2.98-2.92 (m,2H), 2.52-2.40 (m, 3H), 1.98 (t, 2H, J=11.5 Hz), 1.85-1.78 (m, 2H),1.72-1.54 (m, 3H), 1.27 (d, 6H, J=6.3 Hz); ESMS m/e: 550.3 (M+H)⁺; Anal.Calc. for C₃₂H₃₇F₂N₃O₃.0.87HCl: C, 66.84; H, 6.61; N, 7.31. Found: C,66.83; H, 6.48; N, 7.31.

EXAMPLE 147

ISOPROPYL 3-{1-[3-({[1-(2-CHLORO-4-FLUOROPHENYL)CYCLOHEXYL]CARBONYL}AMINO)PROPYL]-4-PIPERIDINYL}PHENYLCARBAMATE: Example 147 was preparedfrom 1-(2-chloro-4-fluorophenyl)cyclohexanecarboxylic acid and isopropyl3-[1-(3-amino propyl)-4-piperidinyl]phenyl carbamate according to theprocedures described in Scheme 9: ESMS m/e: 558.1 (M+H)⁺.

EXAMPLE 148

N-[4-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE:Example 148 was prepared from N-(3-bromopropyl)-2,2-diphenyl acetamideand 2-methyl-N-[4-(4-piperidinyl) phenyl] propanamide according to theprocedures described in Scheme 14: ESMS m/e: 498.3 (M+H)⁺.

EXAMPLE 149

N-[4-(1-{3-[(2,2-DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL]BUTANAMIDE:Example 149 was prepared from N-(3-bromopropyl)-2,2-diphenylacetamideand N-[4-(4-piperidinyl)phenyl]butanamide according to the proceduresdescribed in Scheme 14: ESMS m/e: 498.3 (M+H)⁺.

EXAMPLE 150

N-[5-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)-2-HYDROXYPHENYL]-2-METHYLPROPANAMIDE:Example 150 was prepared from diphenylacetyl chloride andN-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-hydroxyphenyl}-2-methylpropanamideaccording to the procedures described in Scheme 8: ¹H NMR (400 MHz,CDCl₃) δ 8.18 (s, 1H), 7.30-7.11 (m, 10H), 7.10-6.9 (m, 2H), 6.74 (d,1H, J=8.3 Hz), 6.63 (dd, 1H, J=8.3, 2.0 Hz), 4.93 (s, 1H), 3.51 (t, 1H,J=5.4 Hz), 3.36 (quintet, 1H, J=6.5 Hz), 3.24-3.18 (m, 2H), 3.07-3.00(m, 2H), 2.54-2.45 (m, 3H), 2.37-2.28 (m, 1H), 2.19-2.09 (m, 2H),1.79-1.54 (m, 4H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 514.3 (M+H)⁺.

EXAMPLE 151

N-[3-(1-{3-[(3,3-DIPHENYLPROPANOYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL]CYCLOPROPANECARBOXAMIDE: Example 151 was prepared from3,3-diphenylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropane carboxamide according to the procedures described inScheme 9: ESMS m/e: 510.4 (M+H)⁺.

EXAMPLE 152

N-{3-[4-(3-AMINOPHENYL)-1-PIPERIDINYL]PROPYL}-2,2-DIPHENYLACETAMIDE:Example 152 was prepared via hydrogenation of benzyl3-(1-{3-[(diphenylacetyl)amino] propyl}-4-piperidinyl)phenylcarbamateaccording to the procedures described in Scheme 15: ESMS m/e: 428.3(M+H)⁺.

EXAMPLE 153

N-{3-[1-(3-{[(3,4-difluorophenyl)(hydroxy)acetyl]amino}propyl)-4-piperdinyl]-4-methylphenyl}-2-methylpropanamide:Example 153 was prepared from (3,4-difluorophenyl)(hydroxy)acetic acidandN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamideaccording to the procedures described in Scheme 12: ESMS m/e: 488.3(M+H)⁺.

EXAMPLE 154

N-{3-[1-(3-{[hydroxy(diphenyl)acetyl]amino}propyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide: A mixture of hydroxy(diphenyl)acetic acid (100 mg, 0.44mmol) and 1,1′-carbonyldiimidazole (78 mg, 0.48 mmol) in CH₂Cl₂ (5 mL)was stirred at room temperature for 3 h, then a solution ofN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide (140 mg, 0.44 mmol) in CH₂Cl₂ (5 mL) was added. Theresulting mixture was stirred at room temperature for overnight,evaporated in vacuo, and dissolved in a mixture of EtOAc and 1N NaOH.The organic layer was separated, washed twice with water, dried overMgSO₄ and concentrated. The residue was purified over preparative TLC(10% 2M NH3/MeOH in 50% EtOAc/hexane) to give 111 mg (0.21 mmol, 48%) of(N-{3-[1-(3-{[hydroxy(diphenyl)acetyl]amino}propyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide:¹H NMR (400 MHz, CDCl₃) δ 9.22 (s, 1H), 8.14 (s, 1H), 7.80 (s, 1H),7.64-7.48 (m, 4H), 7.32-7.16 (m, 6H), 6.95 (d, 1H, J=8.0 Hz), 6.64 (d,1H, J=8.0 Hz), 5.83-5.62 (br, 1H), 3.54-3.38 (m, 2H), 3.11-2.94 (m, 2H),2.79-2.59 (m, 1H), 2.57-2.41 (m, 2H), 2.26 (s, 3H), 2.29-2.16 (m, 1H),2.16-1.91 (m, 4H), 1.74-1.53 (m, 4H), 0.86 (d, 6H, J=6.8 Hz); ESMS m/e:528.4 (M+H)⁺.

EXAMPLE 155

N-{2,4-difluoro-5-[1-(3-{[hydroxy(diphenyl)acetyl]amino}propyl)-4-piperidinyl]phenyl}-2-methylpropanamide:Example 155 was prepared from hydroxy(diphenyl)acetic acid andN-{5-[1-(3-aminopropyl)-4-piperidinyl]-2,4-difluorophenyl}-2-methylpropanamideaccording to the procedures described in Scheme 12: ¹H NMR (400 MHz,CDCl₃) δ 8.96 (s, 1H), 8.39 (t, 1H, J=8.4 Hz), 7.62-7.45 (m, 4H),7.38-7.18 (m, 7H), 6.85-6.74 (m, 1H), 5.43-5.14 (br, 1H), 3.59-3.39 (m,2H), 3.11-2.97 (m, 2H), 2.97-2.79 (m, 1H), 2.59-2.45 (m, 2H), 2.45-2.29(m, 1H), 2.14-1.86 (m, 4H), 1.81-1.56 (m, 4H), 1.01 (d, 6H, J=7.2 Hz);ESMS m/e: 550.4 (M+H)⁺.

EXAMPLE 156

N-{3-[1-(3-{[bis(4-fluorophenyl)(hydroxy)acetyl]amino}propyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide:Example 156 was prepared from bis(4-fluorophenyl)(hydroxy)acetic acidandN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamideaccording to the procedures described in Scheme 12: ¹H NMR (400 MHz,CDCl₃) δ 9.44 (s, br, 1H), 8.18 (s, 1H), 7.62-7.48 (m, 4H), 7.32 (s,1H), 7.07-7.00 (m, 1H), 7.00-6.89 (m, 4H), 6.72-6.53 (m, 1H), 5.96-5.71(br, 1H), 3.55-3.44 (m, 2H), 3.14-3.02 (m, 2H), 2.83-2.66 (m, 1H),2.63-2.49 (m, 2H), 2.39-2.22 (m, 1H), 2.29 (s, 3H), 2.17-1.98 (m, 4H),1.78-1.59 (m, 4H), 0.92 (d, 6H, J=6.8 Hz); ESMS m/e: 564.4 (M+H)⁺.

EXAMPLE 157

N-(3-{1-[3-({hydroxy[bis(4-methylphenyl)]acetyl}amino)propyl]-4-piperidinyl}-4-methylphenyl)-2-methylpropanamide:Example 157 was prepared from hydroxy[bis(4-methylphenyl)]acetic acidandN-{3-[1-(3-aminopropyl)-4-piperidinyl]4-methylphenyl}-2-methylpropanamideaccording to the procedures described in Scheme 12: ¹H NMR (400 MHz,CDCl₃) δ 8.80-8.59 (s, br, 1H), 7.91 (s, 1H), 7.42 (d, 4H, J=8.4 Hz),7.15 (s, 1H), 7.09 (d, 4H, J=8.0 Hz), 7.04 (d, 1H, J=8.0 Hz), 6.96-6.78(br, 1H), 5.30-5.05 (br, 1H), 3.55-3.41 (m, 2H), 3.15-3.00 (m, 2H),2.82-2.64 (m, 1H), 2.59-2.46 (m, 2H), 2.40-2.27 (m, 1H), 2.30 (s, 6H),2.28 (s, 3H), 2.17-1.95 (m, 4H), 1.83-1.56 (m, 4H), 1.02 (d, 6H, J=6.8Hz); ESMS m/e: 556.4 (M+H)⁺.

EXAMPLE 158

N-{3-[1-(3-{[bis(2-chlorophenyl)(hydroxy)acetyl]amino}propyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide:Example 158 was prepared from bis(2-chlorophenyl)(hydroxy)acetic acidandN-{3-[1-(3-aminopropyl)-4-piperidinyl]4-methylphenyl}-2-methylpropanamideaccording to the procedures described in Scheme 12: ¹H NMR (400 MHz,CDCl₃) δ 8.33 (s, 1H), 7.43-7.18 (m, 1.1H), 7.05 (d, 1H, J=8.0 Hz), 5.03(s, 1H), 3.60-3.49 (m, 2H), 3.03-2.91 (m, 2H), 2.71-2.54 (m, 1H),2.54-2.37 (m, 3H), 2.25 (s, 3H), 2.08-1.91 (m, 2H), 1.84-1.63 (m, 4H),1.63-1.50 (m, 2H), 1.17 (d, 6H, J=6.8 Hz); ESMS m/e: 596.3 (M+H)⁺.

EXAMPLE 159

N-(2,4-difluoro-5-{1-[3-({hydroxy[bis(4-methylphenyl)]acetyl}amino)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide: Example 159 was prepared fromhydroxy[bis(4-methylphenyl)]acetic acid andN-{5-[1-(3-aminopropyl)-4-piperidinyl]-2,4-difluorophenyl}-2-methylpropanamideaccording to the procedures described in Scheme 12: ¹H NMR (400 MHz,CDCl₃) δ 8.78-8.62 (s, br, 1H), 8.37 (t, 1H, J=9.6 Hz), 7.40 (d, 4H,J=8.4 Hz), 7.28 (s, 1H), 7.09 (d, 4H, J=8.0 Hz), 6.84-6.74 (m, 1H),5.14-4.82 (br, 1H), 3.55-3.40 (m, 2H), 3.11-2.94 (m, 2H), 2.94-2.78 (m,1H), 2.59-2.46 (m, 2H), 2.46-2.36 (m, 1H), 2.31 (s, 6H), 2.11-1.91 (m,4H), 1.77-1.61 (m, 4H), 1.04 (d, 6H, J=7.2 Hz); ESMS m/e: 578.4 (M+H)⁺.

EXAMPLE 160

N-{5-[1-(3-{[bis(4-fluorophenyl)(hydroxy)acetyl]amino}propyl)-4-piperidinyl]-2,4-difluorophenyl}-2-methylpropanamide: Example 160 was prepared from bis(4-fluorophenyl) (hydroxy)acetic acid andN-{5-[1-(3-aminopropyl)-4-piperidinyl]2,4-difluoro phenyl}-2-methylpropanamide according to the procedures described in Scheme 12: ¹H NMR(400 MHz, CDCl₃) δ 9.31 (s, br, 1H), 8.44-8.33 (m, 1H), 7.59-7.45 (m,4H), 7.39 (s, 1H), 6.97 (t, 4H, J=8.8 Hz), 6.80 (t, 1H, J=9.6 Hz),5.61-5.36 (br, 1H), 3.57-3.43 (m, 2H), 3.14-2.99 (m, 2H), 2.99-2.84 (m,1H), 2.62-2.47 (m, 2H), 2.47-2.29 (m, 1H), 2.14-1.93 (m, 4H), 1.81-1.59(m, 4H), 0.98 (apparent t, 6H, J=6.8 Hz); ESMS m/e: 586.3 (M+H)⁺.

EXAMPLE 161

2-methyl-N-{4-methyl-3-[1-(3-{[(2S)-2-phenylpropanoyl]amino}propyl)-4-piperidinyl]phenyl}propanamide: Example 161 was prepared from (2S)-2-phenylpropanoic acidand N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4methylphenyl}-2-methylpropanamide according to the procedures describedin Scheme 12: ¹H NMR (400 MHz, CDCl₃) δ 7.61 (s, 1H), 7.47-7.38 (m, 1H),7.37-7.26 (m, 5H), 7.26-7.18 (m, 1H), 7.06 (d, 1H, J=8.0 Hz), 6.74-6.64(m, 1H), 3.64-3.50 (m, 1H), 3.38-3.23 (m, 2H), 2.92 (ABq, 2H), 2.70-2.58(m, 1H), 2.58-2.42 (m, 1H), 2.33 (t, 2H, J=6.4 Hz), 2.26 (s, 3H),2.02-1.88 (m, 2H), 1.76-1.55 (m, 6H), 1.53 (d, 3H, J=7.2 Hz), 1.22 (d,6H, J=6.8 Hz); ESMS m/e: 450.2 (M+H)⁺; HCl salt of2-methyl-N-{4-methyl-3-[1-(3-{[(2S)-2-phenyl propanoyl]amino}propyl)-4-piperidinyl]phenyl}propanamide [α]_(D)=+22.3° (C=1, MeOH)

EXAMPLE 162

(2R)-N-(3-{4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidinyl}propyl)-2-phenylbutanamide: Example 162 was prepared from (2R)-2-phenylbutanoic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide accordingprocedures described in Scheme 12; ESMS m/e: 464.3 (M+H)⁺; HCl salt of(2R)-N-{4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidinyl}propyl)-2-phenylbutanamide[α]_(D)=−24.5° (C=1.1, MeOH)

EXAMPLE 163

(2S)-N-(3-{4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidinyl}propyl)-2-phenylbutanamide:Example 163 was prepared from (2S)-2-phenylbutanoic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamideaccording to the procedures described in Scheme 12; ESMS m/e: 464.4(M+H)⁺; HCl salt of(2S)-N-(3-{4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidinyl}propyl)-2-phenylbutanamide[α]_(D)=+25.00 (C=1, MeOH)

EXAMPLE 164

2-methyl-N-{4-methyl-3-[1-(3-{[(2R)-2-phenylpropanoyl]amino}propyl)-4-piperidinyl]phenyl}propanamide: Example 164 was prepared from (2R)-2-phenylpropanoic acidandN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamideaccording to the procedures described in Scheme 12: ¹H NMR (400 MHz,CDCl₃) δ 7.63 (s, 1H), 7.44 (d, 1H. J=2.0 Hz), 7.38-7.26 (m, 5H),7.26-7.18 (m, 1H), 7.06 (d, 1H, J=8.0 Hz), 6.74-6.63 (m, 1H), 3.63-3.49(m, 1H), 3.38-3.23 (m, 2H), 2.91 (ABq, 2H), 2.71-2.58 (m, 1H), 2.58-2.45(m, 1H), 2.32 (t, 2H, J=6.4 Hz), 2.26 (s, 3H), 2.05-1.87 (m, 2H),1.77-1.55 (m, 6H), 1.53 (d, 3H, J=7.2 Hz), 1.22 (d, 6H, J=6.8 Hz); ESMSm/e: 450.4 (M+H)⁺; HCl salt of2-methyl-N-{4-methyl-3-[1-(3-{[(2R)-2-phenylpropanoyl]amino}propyl)-4-piperidinyl]phenyl}propanamide [α]_(D)=−34.3° (C=1, MeOH)

EXAMPLE 165

N-{5-[1-(3-{[bis(4-fluorophenyl)acetyl]amino}propyl)-4-piperidinyl]-2,4-difluorophenyl}-2-methylpropanamide:Example 165 was prepared from bis(4-fluorophenyl)acetic acid andN-{5-[1-(3-aminopropyl)-4-piperidinyl]-2,4-difluorophenyl}-2-methylpropanamideaccording to the procedures described in Scheme 10: ¹H NMR (400 MHz,CDCl₃) δ 8.25 (t, 1H, J=8.4 Hz), 7.67-7.57 (m, 1H), 7.51 (s, 1H),7.36-7.25 (m, 4H), 7.03-6.91 (m, 4H), 6.81 (t, 1H, J=9.6 Hz), 4.81 (s,1H), 3.45-3.31 (m, 2H), 2.92 (m, 2H), 2.83-2.67 (m, 1H), 2.63-2.47 (m,1H), 2.47-2.33 (m, 2H), 2.05-1.90 (m, 2H), 1.82-1.72 (m, 2H), 1.72-1.56(m, 4H), 1.22 (d, 6H, J=6.8 Hz); ESMS m/e: 570.2 (M+H)⁺.

EXAMPLE 166

(2S)-2-(4-chlorophenyl)-N-(3-{4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidinyl}propyl)propanamide: Example 166 was prepared from(2S)-2-(4-chlorophenyl)propanoic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamideaccording to the procedures described in Scheme 12; [α]_(D)=+5.20(C=1.03, MeOH): ¹H NMR (400 MHz, CDCl₃) δ 7.55 (d, 1H, J=2.0 Hz), 7.46(s, 1H), 7.34-7.24 (m, 4H), 7.23-7.17 (m, 1H), 7.07 (d, 1H, J=8.0 Hz),7.04-6.97 (m, 1H), 3.54 (q, 1H, J=7.2 Hz), 3.41-3.24 (m, 2H), 2.95 (ABq,2H), 2.72-2.59 (m, 1H), 2.57-2.45 (m, 1H), 2.42-2.37 (m, 2H), 2.27 (s,3H), 2.05-1.91 (m, 2H), 1.82-1.55 (m, 6H), 1.50 (d, 3H, J=6.8 Hz), 1.22(d, 6H, J=6.8 Hz); ESMS m/e: 484.3 (M+H)⁺.

EXAMPLE 167

(2R)-2-(4-chlorophenyl)-N-(3-{4-[5-isobutyrylamino)-2-methylphenyl]-1-piperidinyl}propyl)propanamide: Example 167 was prepared from(2R)-2-(4-chlorophenyl)propanoic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4methylphenyl}-2-methylpropanamide according to the procedures describedin Scheme 12; [α]_(D)=−9.3° (C=1.65, MeOH): ¹H NMR (400 MHz, CDCl₃) δ7.55 (s, 1H), 7.36-7.24 (m, 4H), 7.22-7.12 (m, 2H), 7.08 (d, 1H, J=8.0Hz), 6.92 (s, 1H), 3.53 (q, 1H, J=7.2 Hz), 3.42-3.23 (m, 2H), 2.95 (ABq,2H), 2.73-2.59 (m, 1H), 2.57-2.43 (m, 1H), 2.42-2.33 (m, 2H), 2.28 (s,3H), 2.08-1.92 (m, 2H), 1.86-1.56 (m, 6H), 1.51 (d, 3H, J=7.2 Hz), 1.24(d, 6H, J=6.8 Hz); ESMS m/e: 484.3 (M+H)⁺.

EXAMPLE 168

(2S)-2-(4-fluorophenyl)-N-(3-{4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidinyl}propyl)propanamide: Example 168 was prepared from(2S)-2-(4-fluorophenyl)propanoic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamideaccording to the procedures described in Scheme 12; [α]_(D)=+13.5°(C=1.02, MeOH): ¹H NMR (400 MHz, CDCl₃) δ 7.58-7.49 (m, 2H), 7.37-7.29(m, 2H), 7.26-7.19 (m, 1H), 7.06 (d, 1H, J=8.0 Hz), 7.04-6.92 (m, 3H),3.56 (t, 1H, J=6.8 Hz), 3.43-3.23 (m, 2H), 2.95 (ABq, 2H), 2.63-2.59 (m,1H), 2.59-2.45 (m, 1H), 2.37 (t, 2H, J=6.0 Hz), 2.27 (s, 3H), 2.07-1.90(m, 2H), 1.82-1.57 (m, 6H), 1.50 (d, 3H, J=7.2 Hz), 1.22 (d, 6H, J=7.2Hz); ESMS m/e: 468.3 (M+H)⁺.

EXAMPLE 169

(2R)-2-(4-fluorophenyl)-N-(3-{4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidinyl}propyl)propanamide: Example 169 was prepared from(2R)-2-(4-fluorophenyl)propanoic acid andN-{3-[1-(aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamideaccording to the procedures described in Scheme 12; [α]_(D)=−9.1°(C=1.65, MeOH): ¹H NMR (400 MHz, CDCl₃) δ 7.51 (d, 1H, J=2.0 Hz),7.37-7.28 (m, 2H), 7.23-7.14 (m, 2H), 7.08 (d, 1H. J=8.0 Hz), 7.05-6.96(m, 2H), 6.90-6.82 (m, 1H), 3.54 (q, 1H, J=7.2 Hz), 3.43-3.23 (m, 2H),2.95 (ABq, 2H), 2.73-2.59 (m, 1H), 2.57-2.42 (m, 1H), 2.42-2.32 (m, 2H),2.28 (s, 3H), 2.07-1.91 (m, 2H), 1.83-1.57 (m, 6H), 1.51 (d, 3H, J=7.2Hz), 1.23 (d, 6H, J=6.8 Hz); ESMS m/e: 468.3 (M+H)⁺.

EXAMPLE 170

N-[5-(1-{3-[(diphenylacetyl)amino]propyl}-4-piperidinyl)-3-pyridinyl]-2-methylpropanamide: Example 170 was prepared fromN-(3-bromopropyl)-2,2-diphenylacetamide and2-methyl-N-[5-(4-piperidinyl)-3-pyridinyl]propanamide according to theprocedures described in Scheme 14: ¹H NMR (400 MHz, CDCl₃) δ 8.47-8.42(m, 1H), 8.21-8.16 (m, 1H), 8.09 (s, 1H), 7.59 (s, 1H), 7.35-7.20 (m,10H), 6.87 (s, 1H), 4.91 (s, 1H), 3.46-3.36 (m, 2H), 3.01-2.92 (m, 2H),2.62-2.47 (m, 2H), 2.47-2.37 (m, 2H), 2.11-1.94 (m, 4H), 1.86-1.59 (m,4H), 1.25 (d, 6 H, J=7.2 Hz); ESMS m/e: 499.4 (M+H)⁺.

EXAMPLE 171

N-[3-(1-{3-[(diphenylacetyl)amino]propyl}-4-piperidinyl)-2,4,6-trifluorophenyl]-2-methylpropanamide:Example 171 was prepared from N-(3-bromopropyl)-2,2-diphenylacetamideand 2-methyl-N-[2,4,6-trifluoro-3-(4-piperidinyl)phenyl]propanamideaccording to the procedures described in Scheme 14; ESMS m/e: 552.3(M+H)⁺.

EXAMPLE 172

N-{5-[1-(3-{[bis(4-fluorophenyl)acetyl]amino}propyl)-4-piperidinyl]-3-pyridinyl}-2-methylpropanamide:Example 172 was prepared from N-(3-bromopropyl)-2,2-bis(4-fluoro phenyl)acetamide and 2-methyl-N-[5-(4-piperidinyl)-3-pyridinyl]propanamideaccording to the procedures described in Scheme 14: ¹H NMR (400 MHz,CDCl₃) δ 8.39 (s, 1H), 8.19 (s, 1H), 8.17 (S, 1H), 7.95 (s, 1H),7.31-7.20 (m, 5H), 7.04-6.94 (m, 4H), 4.82 (s, 1H), 3.46-3.35 (m, 2H),2.98-2.92 (m, 2H), 2.62-2.48 (m, 2H), 2.48-2.38 (m, 2H), 2.09-1.95 (m,2H), 1.87-1.76 (m, 2H), 1.76-1.55 (m, 4H), 1.25 (d, 6H, J=7.6 Hz); ESMSm/e: 535.4 (M+H)⁺.

EXAMPLE 173

N-{3-[1-(3-{[bis(4-fluorophenyl)acetyl]amino}propyl)-4-piperidinyl]-2,4,6-trifluorophenyl}-2-methylpropanamide:Example 173 was prepared from N-(3-bromopropyl)-2,2-bis(4-fluorophenyl)acetamide and2-methyl-N-[2,4,6-trifluoro-3-(4-piperidinyl)phenyl]propanamideaccording to the procedures described in Scheme 14; ESMS m/e: 588.3(M+H)⁺.

EXAMPLE 174

N-{3-[1-(3-{[amino(diphenyl)acetyl]amino}propyl)-4-piperidinyl]-4-fluorophenyl}cyclopropane carboxamide: Example 174 was prepared fromamino(diphenyl)acetic acid andN-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluoropheny}cyclopropanecarboxamide according to the procedures described in Scheme12; ESMS m/e: 529.4 (M+H)⁺.

EXAMPLE 175

N-{3-[1-(3-{[(4-fluorophenyl)acetyl]amino}propyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide: Example 175 was prepared from (4-fluorophenyl)acetic acidandN{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamideaccording to the procedures described in Scheme 12: ¹H NMR (400 MHz,CDCl₃) δ 7.38 (s, 1H), 7.32 (s, 1H), 7.28-7.16 (m, 3H), 7.04-6.90 (m,3H), 6.86 (s, 1H), 3.47 (s, 2H), 3.27 (q, 2H, J=6.0 Hz), 2.95 (d, 2H,J=11.6 Hz), 2.69-2.53 (m, 1H), 2.50-2.32 (m, 3H), 2.19 (s, 3H),2.09-1.94 (m, 2H), 1.74-1.53 (m, 6H), 1.15 (d, 6H, J=7.2 Hz); ESMS m/e:454.3 (M+H)⁺.

EXAMPLE 176

N-{5-[1-(3-{[hydroxy(diphenyl)acetyl]amino}propyl)-4-piperidinyl]-3-pyridinyl}-2-methylpropanamide: Example 176 was prepared from hydroxy(diphenyl)acetic acidand N-{5-[1-(3-aminopropyl)piperidinyl]-3-pyridinyl}-2-methylpropanamideaccording procedures described in Scheme 12; ESMS m/e: 515.4 (M+H)⁺.

EXAMPLE 177

N-{5-[1-(3-{[bis(4-fluorophenyl)(hydroxy)acetyl]amino}propyl)-4-piperidinyl]-3-pyridinyl}-2-methylpropanamide:Example 177 was prepared from bis(4-fluorophenyl) (hydroxy)acetic acidand N-{5-[1-(3-aminopropyl)-4-piperidinyl]-3-pyridinyl}-2-methylpropanamide according procedures described in Scheme 12; ESMS m/e: 551.3(M+H)⁺.

EXAMPLE 178

N-(5-{4-[3-({hydroxy[bis(4-methylphenyl)]acetyl}amino)propyl]-4-piperidinyl}-3-pyridinyl)-2-methylpropanamide:Example 178 was prepared from hydroxy[bis(4-methylphenyl)]acetic acidand N-{5-[1-(3-aminopropyl)-4-piperidinyl]3-pyridinyl}2-methylpropanamide according procedures described in Scheme 12; ESMS m/e: 543.4(M+H)⁺.

II. Synthetic Methods for General Structures

The examples described in the experimental section are merelyillustrative of the methods used to synthesize MCH1 antagonists.Additional compounds of the invention can be obtained by the generalsynthetic procedures described herein or by incorporating variationsinto these methods. It may be necessary to incorporate protection anddeprotection strategies into the generalized synthetic methods in orderto synthesize additional examples containing potentially reactivesubstituents such as amino, amido, carboxylic acid, and hydroxyl groups.Methods for protection and deprotection of such groups are well-known inthe art, and may be found, for example in Green, T. W. and Wuts, P. G.M. (1991) Protection Groups in Organic Synthesis, 2^(nd) Edition JohnWiley & Sons, New York.

III. Oral Compositions

As a specific embodiment of an oral composition of a compound of thisinvention, 100 mg of one of the compounds described herein is formulatedwith sufficient finely divided lactose to provide a total amount of 580to 590 mg to fill a size 0 hard gel capsule.

IV. Pharmacological Evaluation of Compounds at Cloned Rat MCH1 Receptor

The pharmacological properties of the compounds of the present inventionwere evaluated at the cloned rat MCH1 receptor using the protocolsdescribed below.

Host Cells

A broad variety of host cells can be used to study heterologouslyexpressed proteins. These cells include but are not restricted toassorted mammalian lines such as: Cos-7, CHO, LM(tk-), HEK293, Peakrapid 293, etc.; insect cell lines such as: Sf9, Sf21, etc.; amphibiancells such as xenopus oocytes; and others. COS 7 cells are grown on 150mm plates in DMEM with supplements (Dulbecco's Modified Eagle Mediumwith 10% bovine calf serum, 4 mM glutamine, 100 units/ml penicillin/100Fg/ml streptomycin) at 37° C., 5% CO₂. Stock plates of COS-7 cells aretrypsinized and split 1:6 every 3-4 days. Human embryonic kidney 293cells are grown on 150 mm plates in DMEM with supplements (10% bovinecalf serum, 4 mM glutamine, 100 units/ml penicillin/100 Fg/mlstreptomycin) at 37° C., 5% CO₂. Stock plates of 293 cells aretrypsinized and split 1:6 every 3-4 days.

Human embryonic kidney Peak rapid 293 (Peakr293) cells are grown on 150mm plates in DMEM with supplements (10% fetal bovine serum, 10%L-glutamine, 50 Fg/ml gentamycin) at 37° C., 5% CO₂. Stock plates ofPeak rapid 293 cells are trypsinized and split 1:12 every 3-4 days.Mouse fibroblast LM(tk-) cells are grown on 150 mm plates in DMEM withsupplements (Dulbecco's Modified Eagle Medium with 10% bovine calfserum, 4 mM glutamine, 100 units/ml penicillin/100 Fg/ml streptomycin)at 37° C., 5% CO₂. Stock plates of LM(tk-) cells are trypsinized andsplit 1:10 every 3-4 days. Chinese hamster ovary (CHO) cells were grownon 150 mm plates in HAM=s F-12 medium with supplements (10% bovine calfserum, 4 mM L-glutamine and 100 units/ml penicillin/100 Fg/mlstreptomycin) at 37° C., 5% CO₂. Stock plates of CHO cells aretrypsinized and split 1:8 every 3-4 days. Mouse embryonic fibroblastNIH-3T3 cells are grown on 150 mm plates in Dulbecco=s Modified EagleMedium (DMEM) with supplements (10% bovine calf serum, 4 mM glutamine,100 units/ml penicillin/100 Fg/ml streptomycin) at 37° C., 5% CO₂. Stockplates of NIH-3T3 cells are trypsinized and split 1:15 every 3-4 days.Sf9 and Sf21 cells are grown in monolayers on 150 mm tissue culturedishes in TMN-FH media supplemented with 10% fetal calf serum, at 27°C., no CO₂. High Five insect cells are grown on 150 mm tissue culturedishes in Ex-Cell 400™ medium supplemented with L-Glutamine, also at 27°C., no CO₂. In some cases, cell lines that grow as adherent monolayerscan be converted to suspension culture to increase cell yield andprovide large batches of uniform assay material for routine receptorscreening projects.

Transient Expression

DNA encoding proteins to be studied can be transiently expressed in avariety of mammalian, insect, amphibian and other cell lines by severalmethods including but not restricted to; calcium phosphate-mediated,DEAE-dextran mediated, Liposomal-mediated, viral-mediated,electroporation-mediated and microinjection delivery. Each of thesemethods may require optimization of assorted experimental parametersdepending on the DNA, cell line, and the type of assay to besubsequently employed. A typical protocol for the calcium phosphatemethod as applied to Peak rapid 293 cells is described as follows:Adherent cells are harvested approximately twenty-four hours beforetransfection and replated at a density of 3.5×10⁶ cells/dish in a 150 mmtissue culture dish and allowed to incubate over night at 37° C. at 5%CO₂. 250 Fl of a mixture of CaCl₂ and DNA (15 Fg DNA in 250 mM CaCl₂) isadded to a 5 ml plastic tube and 500 Fl of 2×HBS (280 mM NaCl, 10 mMKCl, 1.5 mM Na₂HPO₄, 12 mM dextrose, 50 mM HEPES) is slowly added withgentle mixing. The mixture is allowed to incubate for 20 minutes at roomtemperature to allow a DNA precipitate to form. The DNA precipitatemixture is then added to the culture medium in each plate and incubatedfor 5 hours at 37° C., 5% CO₂. After the incubation, 5 ml of culturemedium (DMEM, 10% FBS, 10% L-glut and 50 μg/ml gentamycin) is added toeach plate. The cells are then incubated for 24 to 48 hours at 37° C.,5% CO₂. A typical protocol for the DEAE-dextran method as applied toCos-7 cells is described as follows; Cells to be used for transfectionare split 24 hours prior to the transfection to provide flasks which are70-80% confluent at the time of transfection. Briefly, 8 Fg of receptorDNA plus 8 Fg of any additional DNA needed (e.g. G_(α) proteinexpression vector, reporter construct, antibiotic resistance marker,mock vector, etc.) are added to 9 ml of complete DMEM plus DEAE-dextranmixture (10 mg/ml in PBS). Cos-7 cells plated into a T225 flask(sub-confluent) are washed once with PBS and the DNA mixture is added toeach flask. The cells are allowed to incubate for 30 minutes at 37° C.,5% CO₂. Following the incubation, 36 ml of complete DMEM with 80 FMchloroquine is added to each flask and allowed to incubate an additional3 hours. The medium is then aspirated and 24 ml of complete mediumcontaining 10% DMSO for exactly 2 minutes and then aspirated. The cellsare then washed 2 times with PBS and 30 ml of complete DMEM added toeach flask. The cells are then allowed to incubate over night. The nextday the cells are harvested by trypsinization and reseeded as neededdepending upon the type of assay to be performed.

A typical protocol for liposomal-mediated transfection as applied to CHOcells is described as follows; Cells to be used for transfection aresplit 24 hours prior to the transfection to provide flasks which are70-80% confluent at the time of transfection. A total of 10 Fg of DNAwhich may include varying ratios of receptor DNA plus any additional DNAneeded (e.g. G, protein expression vector, reporter construct,antibiotic resistance marker, mock vector, etc.) is used to transfecteach 75 cm² flask of cells. Liposomal mediated transfection is carriedout according to the manufacturer's recommendations (LipofectAMINE,GibcoBRL, Bethesda, Md.). Transfected cells are harvested 24 hours posttransfection and used or reseeded according the requirements of theassay to be employed. A typical protocol for the electroporation methodas applied to Cos-7 cells is described as follows; Cells to be used fortransfection are split 24 hours prior to the transfection to provideflasks which are subconfluent at the time of transfection. The cells areharvested by trypsinization resuspended in their growth media andcounted. 4×10⁶ cells are suspended in 300 Fl of DMEM and placed into anelectroporation cuvette. 8 Fg of receptor DNA plus 8 Fg of anyadditional DNA needed (e.g. G_(α) protein expression vector, reporterconstruct, antibiotic resistance marker, mock vector, etc.) is added tothe cell suspension, the cuvette is placed into a BioRad Gene Pulser andsubjected to an electrical pulse (Gene Pulser settings: 0.25 kV voltage,950 FF capacitance). Following the pulse, 800 Fl of complete DMEM isadded to each cuvette and the suspension transferred to a sterile tube.Complete medium is added to each tube to bring the final cellconcentration to 1×10⁵ cells/100 Fl. The cells are then plated as neededdepending upon the type of assay to be performed.

A typical protocol for viral mediated expression of heterologousproteins is described as follows for baculovirus infection of insect Sf9cells. The coding region of DNA encoding the receptor disclosed hereinmay be subcloned into pBlueBacIII into existing restriction sites orsites engineered into sequences 5′ and 3′ to the coding region of thepolypeptides. To generate baculovirus, 0.5 Fg of viral DNA (BaculoGold)and 3 Fg of DNA construct encoding a polypeptide may be co-transfectedinto 2×10⁶ Spodoptera frugiperda insect Sf9 cells by the calciumphosphate co-precipitation method, as outlined in by Pharmingen (in“Baculovirus Expression Vector System: Procedures and Methods Manual”).The cells then are incubated for 5 days at 27° C. The supernatant of theco-transfection plate may be collected by centrifugation and therecombinant virus plaque purified. The procedure to infect cells withvirus, to prepare stocks of virus and to titer the virus stocks are asdescribed in Pharmingen=s manual. Similar principals would in generalapply to mammalian cell expression via retro-viruses, Simliki forestvirus and double stranded DNA viruses such as adeno-, herpes-, andvacinia-viruses, and the like.

Stable Expression

Heterologous DNA can be stably incorporated into host cells, causing thecell to perpetually express a foreign protein. Methods for the deliveryof the DNA into the cell are similar to those described above fortransient expression but require the co-transfection of an ancillarygene to confer drug resistance on the targeted host cell. The ensuingdrug resistance can be exploited to select and maintain cells that havetaken up the heterologous DNA. An assortment of resistance genes areavailable including but not restricted to Neomycin, Kanamycin, andHygromycin. For the purposes of receptor studies, stable expression of aheterologous receptor protein is carried out in, but not necessarilyrestricted to, mammalian cells including, CHO, HEK293, LM(tk-), etc.

Cell Membrane Preparation

For binding assays, pellets of transfected cells are suspended inice-cold buffer (20 mM Tris.HCl, 5 mM EDTA, pH 7.4) and homogenized bysonication for 7 sec. The cell lysates are centrifuged at 200×g for 5min at 4° C. The supernatants are then centrifuged at 40,000×g for 20min at 4° C. The resulting pellets are washed once in the homogenizationbuffer and suspended in binding buffer (see methods for radioligandbinding). Protein concentrations are determined by the method ofBradford (1976) using bovine serum albumin as the standard. Bindingassays are usually performed immediately, however it is possible toprepare membranes in batch and store frozen in liquid nitrogen forfuture use.

Radioligand Binding Assays

Radioligand binding assays for the rat MCH1 receptor were carried outusing plasmid pcDNA3.1-rMCH1-f (ATCC Patent Deposit Designation No.PTA-3505). Plasmid pcDNA3.1-rMCH1-f comprises the regulatory elementsnecessary for expression of DNA in a mammalian cell operatively linkedto DNA encoding the rat MCH1 receptor so as to permit expressionthereof. Plasmid pcDNA3.1-rMCH1-f was deposited on Jul. 5, 2001, withthe American Type Culture Collection (ATCC), 12301 Parklawn Drive,Rockville, Md. 20852, U.S.A. under the provisions of the Budapest Treatyfor the International Recognition of the Deposit of Microorganisms forthe Purposes of Patent Procedure and was accorded ATCC Patent DepositDesignation No. PTA-3505. Binding assays can also be performed asdescribed hereinafter using plasmid pEXJ.HR-TL231 (ATCC Accession No.203197) Plasmid pEXJ.HR-TL231 encodes the human MCH1 receptor and wasdeposited on Sep. 17, 1998, with the American Type Culture Collection(ATCC), 12301 Parklawn Drive, Rockville, Md. 20852, U.S.A. under theprovisions of the Budapest Treaty for the International Recognition ofthe Deposit of Microorganisms for the Purposes of Patent Procedure andwas accorded ATCC Accession No. 203197. Human embryonic kidney Peakrapid 293 cells (Peakr293 cells) were transiently transfected with DNAencoding the MCH1 receptor utilizing the calcium phosphate method andcell membranes were prepared as described above. Binding experimentswith membranes from Peakr293 cells transfected with the rat MCH1receptor were performed with 0.08 nM [³H]Compound A (the synthesis ofCompound A is described in detail below) using an incubation bufferconsisting of 50 mM Tris pH 7.4, 10 mM MgCl₂, 0.16 mM PMSF, 1 mM 1,10phenantroline and 0.2% BSA. Binding was performed at 25° C. for 90minutes. Incubations were terminated by rapid vacuum filtration overGF/C glass fiber filters, presoaked in 5% PEI using 50 nM Tris pH 7.4 aswash buffer. In all experiments, nonspecific binding is defined using 10pM Compound A.

Functional Assays

Cells may be screened for the presence of endogenous mammalian receptorusing functional assays. Cells with no or a low level of endogenousreceptor present may be transfected with the exogenous receptor for usein functional assays. A wide spectrum of assays can be employed toscreen for receptor activation. These range from traditionalmeasurements of phosphatidyl inositol, cAMP, Ca⁺⁺, and K⁺, for example;to systems measuring these same second messengers but which have beenmodified or adapted to be higher throughput, more generic, and moresensitive; to cell based platforms reporting more general cellularevents resulting from receptor activation such as metabolic changes,differentiation, and cell division/proliferation, for example; to highlevel organism assays which monitor complex physiological or behavioralchanges thought to be involved with receptor activation includingcardiovascular, analgesic, orexigenic, anxiolytic, and sedation effects,for example.

Radioligand Binding Assay Results

The compounds described above were assayed using cloned rat MCH1. Thebinding affinities of the compounds are shown in Table I. TABLE IExample No. Ki(MCH-1, nM) 1 1.3 2 2.4 3 2.5 4 2.5 5 3.1 6 5.6 7 7.9 811.7 9 71.6 10 83.0 11 8.4 12 13.9 13 11.8 14 2.7 15 8.9 16 1038 17 1.818 31.5 19 23.4 20 90.5 21 0.7 22 136.5 23 13.1 24 4.7 25 2.1 26 18.7 271.1 28 0.4 29 2.3 30 5.3 31 8.2 32 0.6 33 495.6 34 2.3 35 0.4 36 11.0 3719.5 38 28.4 39 32.2 40 7.9 41 39.9 42 34.3 43 13.7 44 19.7 45 4.0 4644.5 47 25.6 48 2.8 49 14.8 50 1.9 51 11.8 52 4.1 53 1.1 54 2.2 55 0.356 4.5 57 0.5 58 45.9 59 4.3 60 41.3 61 63.3 62 31.7 63 150.0 64 70.7 654.9 66 24.4 67 9.9 68 16.9 69 39.9 70 26.7 71 54.5 72 52.3 73 32.4 7434.3 75 4.7 76 48.0 77 30.7 78 6.7 79 5.9 80 7.7 81 3.2 82 8.6 83 10.384 12.6 85 4.6 86 3.2 87 6.4 88 23.0 89 10.8 90 52.2 91 2.9 92 2.6 934.9 94 3.1 95 23.5 96 2.6 97 3.6 98 4.3 99 2.9 100 5.0 101 11.2 102 7.9103 8.0 104 0.9 105 2.8 106 19.0 107 101.2 108 1.9 109 4.7 110 50.4 1111.2 112 3.2 113 0.8 114 4.0 115 6.9 116 18.9 117 17.9 118 13.9 119 18.6120 0.4 121 10.2 122 4.8 123 2.8 124 39.9 125 124.5 126 3.0 127 175.0128 2.9 129 4.5 130 2.6 131 4.0 132 0.6 133 5.9 134 2.4 135 5.2 136 48.7137 11.8 138 10.2 139 33.4 140 180.0 141 8.8 142 77.4 143 6.2 144 33.2145 26.9 146 6.2 147 42.0 148 144.0 149 467.0 150 NA 151 62.0 152 115.0153 20.3 154 0.5 155 6.8 156 0.7 157 1.1 158 9.4 159 5.4 160 3.6 16124.4 162 8.6 163 20.0 164 14.6 165 1.1 166 5.7 167 18.7 168 12.1 16935.9 170 19.1 171 9.1 172 2.5 173 2.5 174 NA 175 24.7 176 34.6 177 5.3178 16.0V. Synthesis of Radiolabeled Compound A

Described below is the synthesis of Compound A. Compound A is theradiolabeled compound that was used in the radioligand binding assaysdescribed above.

N-[3-(1,2,3,6-TETRAHYDRO-4-PYRIDINYL)PHENYL]ACETAMIDE: The reaction ofsaturated of aqueous Na₂CO₃ solution (25 mL), tert-butyl4-{[(trifluoromethyl)sulfonyl]oxy}-1,2,3,6-tetrahydro-1-pyridine-carboxylate(20 mmol), 3-acetamidophenylboronic acid (30 mmol) andtetrakis-triphenylphosphine palladium (0) (1.15 g) in dimethoxy ethane(40 mL) at reflux temperature overnight gave tert-butyl4-[3-(acetylamino)phenyl]-3,6-dihydro-1(2H-pyridine carboxylate.Deprotection of the BOC group using HCl in dioxane followed bybasification (pH 11-12) gave the desired product. TERT-BUTYLN-(3-BROMOPROPYL)CARBAMATE: was prepared from 3-bromopropylaminehydrobromide and BOC₂O in the presence of base in dichloromethane.

N-{3-[1-(3-AMINOPROPYL)-1,2,3,6-TETRAHYDRO-4-PYRIDINYL]PHENYL}ACETAMIDE:The reaction of tert-butyl N-(3-bromopropyl)carbamate andN-[3-(1,2,3,6-tetrahydro-4-pyridinyl) phenyl]acetamide in refluxingdioxane with catalytic Bu₄NI and base to give tert-butyl3-(4-[3-(acetylamino)phenyl]-3,6-dihydro-1(2H)-pyridinyl)propylcarbamate.Deprotection of the BOC group using HCl in dioxane followed bybasification (pH 11-12) gave the desired product.METHYL(4S)-3-({[3-(4-[3-(ACETYLAMINO)PHENYL]-3,6-DIHYDRO-1(2H)-PYRIDINYL)PROPYL]AMINO}CARBONYL)-4-(3,4-DIFLUOROPHENYL)-6-(METHOXYMETHYL)-2-OXO-1,2,3,4-TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: Prepared fromthe reaction of 5-methyl 1-(4-nitrophenyl)(6S)-6-(3,4-difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylate(describe in PCT Publication No. WO 00/37026, published Jun. 29, 2000)andN-{3-[1-(3-aminopropyl)-1,2,3,6-tetrahydro-4-pyridinyl]phenyl}acetamide:¹H NMR δ 8.90 (t, 1H, J=3.6 Hz), 7.75 (s, 1H), 7.50-7.00 (m, 8H), 6.68(s, 1H), 6.03 (br s, 1H), 4.67 (s, 2H), 3.71 (s, 3H), 3.47 (s, 3H), 3.38(ABm, 2H), 3.16 (m, 2H), 2.71 (t, 2H, J=5.4 Hz), 2.56 (m, 4H), 2.35-1.90(br, 2H), 2.17 (s, 3H), 1.82 (p, 2H, J=7.2 Hz); ESMS, 612.25(M+H)⁺.TRITIATED METHYL(4S)-3-{[(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)AMINO]CARBONYL}-4-(3,4-DIFLUOROPHENYL)-6-(METHOXYMETHYL)-2-OXO-1,2,3,4-TETRAHYDRO-5-PYRIMIDINECARBOXYLATE([³H] COMPOUND A): This radiochemical synthesis was carried out byAmersham Pharmacia Biotech, Cardiff, Wales. A methanolic solution ofmethyl(4S)-3-({[3-(4-[3-(acetylamino)phenyl]-3,6-dihydro-1(2H)-pyridinyl)propyl]amino}carbonyl)-4-(3,4-difluorophenyl)-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate was exposed totritium gas at 1 atmosphere pressure in the presence of 5% palladium oncarbon with stirring overnight to give the tritiated methyl(4S)-3-{[(3-{4-[3(acetylamino)phenyl]-1-piperidinyl}propyl)amino]carbonyl}-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrehydro-5-pyrimidinecarboxylate ((+)-isomer).After purification by reverse phase HPLC (Hypersil ODS, 4.6×100 mm,methanol:H₂O:Et₃N 10:90:1 to 100:0:1 in 15 min at 1.0 mL/min, withradlochemical and UV detection), this product was used as a radioligandin the MCH1 binding assays. The same procedure was carried out with H₂gas in place of ³H₂ to afford the non-radioactive version of Compound A.

VI. In-Vivo Methods

The following in vivo methods were performed to predict the efficacy ofMCH1 antagonists for the treatment of obesity (3-day body weight andsweetened condensed milk), depression (forced swim test), anxiety(social interaction test), and urinary disorders (DIRC and CSTI).

Effects of MCH1 Antagonists on Body Weight (3 Day)

Male Long Evans rats (Charles River) weighing 180-200 grams were housedin groups of four on a 12-hour light/dark cycle with free access to foodand water. Test compounds were administered twice daily via i.p.injection, 1 hour before the dark cycle and 2 hours after lights on, forthree days. All rats were weighed daily after each morning injection.Overall results were expressed as body weight (grams) gained per day(mean±SEM) and were analyzed by two-way ANOVA. Data for each time pointwere analyzed by one-way ANOVA followed by post hoc Newman-Keuls test.The data were analyzed using the GraphPad Prism (v2.01) (GraphPadSoftware, Inc., San Diego, Calif.). All data were presented asmeans±S.E.M.

Effects of MCH1 Antagonists on Consumption of Sweetened Condensed Milk

Male C57BL/6 mice (Charles River) weighing 17-19 grams at the start ofexperiments were housed in groups of four or five on a 12 hourlight/dark cycle with free access to food and water. For 7 days, micewere weighed, placed in individual cages and allowed to drink sweetenedcondensed milk (Nestle, diluted 1:3 with water) for 1 hour, 24 hoursinto the light cycle. The amount of milk consumed was determined byweighing the milk bottle before and after each drinking bout. On thetest day, mice received i.p. injections of Test Compound (3, 10 or 30mg/kg in 0.01% lactic acid), vehicle (0.01% lactic acid) ofd-fenfluramine (10 mg/kg in 0.01% lactic acid) 30 min. prior to exposureto milk. The amount of milk consumed on the test day (in mls milk/kgbody weight) was compared to the baseline consumption for each mousedetermined on the previous 2 days. Data for each time point wereanalyzed by one-way ANOVA.

Forced Swim Test (FST) in the Rat

Animals

Male Sprague-Dawley rats (Taconic Farms, NY) were used in allexperiments. Rats were housed 5 per cage and maintained on a 12:12-hlight-dark cycle. Rats were handled for 1 minutes each day for 4 daysprior to behavioral testing.

Drug Administration

Animals were randomly assigned to receive a single i.p. administrationof vehicle (2.5% EtOH/2.5% Tween-80), imipramine (positive control; 60mg/kg), or Test Compound 60 minutes before the start of the 5 minutetest period. All injections were given using 1 cc tuberculin syringewith 26⅜ gauge needles (Becton-Dickinson, VWR Scientific, Bridgeport,N.J.). The volume of injection was 1 ml/kg.

Experimental Design

The procedure used in this study was similar to that previouslydescribed (Porsolt, et al., 1978), except the water depth was 31 cm inthis procedure. The greater depth in this test prevents the rats fromsupporting themselves by touching the bottom of the cylinder with theirfeet. Swim sessions were conducted by placing rats in individualplexiglass cylinders (46 cm tall×20 cm in diameter) containing 23-25° C.water 31 cm deep. Swim tests were conducted always between 900 and 1700hours and consisted of an initial 15-min conditioning test followed 24 hlater by a 5-minute test. Drug treatments were administered 60 minutesbefore the 5-minute test period. Following all swim sessions, rats wereremoved from the cylinders, dried with paper towels and placed in aheated cage for 15 minutes and returned to their home cages. All testsessions were videotaped using a color video camera and recorded forscoring later.

Behavioral Scoring

The rat's behavior was rated at 5-second intervals during the 5-minutetest by a single individual, who was blind to the treatment condition.Scored behaviors were:

-   -   1. Immobility—rat remains floating in the water without        struggling and was only making those movements necessary to keep        its head above water,    -   2. Climbing—rat was making active movements with its forepaws in        and out of the water, usually directed against the walls;    -   3. Swimming—rat was making active swimming motions, more than        necessary to merely maintain its head above water, e.g. moving        around in the cylinder; and    -   4. Diving—entire body of the rat was submerged.        Data Analysis

The forced swim test data (immobility, swimming, climbing, diving) weresubjected to a randomized, one-way ANOVA and post hoc tests conductedusing the Newman-Keuls test. The data were analyzed using the GraphPadPrism (v2.01) (GraphPad Software, Inc., San Diego, Calif.). All datawere presented as means±S.E.M. All data were presented as means±S.E.M.

Forced Swim Test (FST) in the Mouse

Animals

DBA/2 mice (Taconic Farms, NY) were used in all experiments. Animalswere housed 5 per cage in a controlled environment under a 12:12 hourlight:dark cycle. Animals were handled 1 min each day for 4 days priorto the experiment. This procedure included a mock gavage with a 1.5 inchfeeding tube.

Drug Administration

Animals were randomly assigned to receive a single administration ofvehicle (5% EtOH/5% Tween-80), Test Compound, or imipramine (60 mg/kg)by oral gavage 1 hour before the swim test.

Experimental Design

The procedure for the forced swim test in the mouse was similar to thatdescribed above for the rat, with some modifications. The cylinder usedfor the test was a 1-liter beaker (10.5 cm diameter×15 cm height) fillto 800 ml (10 cm depth) of 23-25° C. water. Only one 5-minute swim testwas conducted for each mouse, between 1300 and 1700 hours. Drugtreatments were administered 30-60 minutes before the 5-minute testperiod. Following all swim sessions, mice were removed from thecylinders, dried with paper towels and placed in a heated cage for 15minutes. All test sessions were videotaped using a Sony color videocamera and recorder for scoring later.

Behavioral Scoring

The behavior during minutes 2-5 of the test was played back on a TVmonitor and scored by the investigator. The total time spent immobile(animal floating with only minimal movements to remain afloat) andmobile (swimming and movements beyond those required to remain afloat)were recorded.

Data Analysis

The forced swim test data (time exhibiting immobility, mobility;seconds) were subjected to a randomized, one-way ANOVA and post hoctests conducted using the Newman-Keuls test. The data were analyzedusing the GraphPad Prism (v2.01) (GraphPad Software, Inc., San Diego,Calif.). All data were presented as means±S.E.M.

Social Interaction Test (SIT)

Rats are allowed to acclimate to the animal care facility for 5 days andare housed singly for 5 days prior to testing. Animals are handled for 5minutes per day. The design and procedure for the Social InteractionTest is carried out as previously described by Kennett, et al. (1997).On the test day, weight matched pairs of rats (±5%), unfamiliar to eachother, are given identical treatments and returned to their home cages.Animals are randomly divided into 5 treatment groups, with 5 pairs pergroup, and are given one of the following i.p. treatments: Test Compound(10, 30 or 100 mg/kg), vehicle (1 ml/kg) or chlordiazepoxide (5 mg/kg).Dosing is 1 hour prior to testing. Rats are subsequently placed in awhite perspex test box or arena (54×37×26 cm), whose floor is divided upinto 24 equal squares, for 15 minutes. An air conditioner is used togenerate background noise and to keep the room at approximately 74° F.All sessions are videotaped using a JVC camcorder (model GR-SZ1, ElmwoodPark, N.J.) with either TDK (HG ultimate brand) or Sony 30 minutevideocassettes. All sessions are conducted between 1300-1630 hours.Active social interaction, defined as grooming, sniffing, biting,boxing, wrestling, following and crawling over or under, is scored usinga stopwatch (Sportsline model no. 226, 1/100 sec. discriminability). Thenumber of episodes of rearing (animal completely raises up its body onits hind limbs), grooming (licking, biting, scratching of body), andface washing (i.e. hands are moved repeatedly over face), and number ofsquares crossed are scored. Passive social interaction (animals arelying beside or on top of each other) is not scored. All behaviors areassessed later by an observer who is blind as to the treatment of eachpair. At the end of each test, the box is thoroughly wiped withmoistened paper towels.

Animals

Male albino Sprague-Dawley rats (Taconic Farms, NY) are housed in pairsunder a 12 hr light dark cycle (lights on at 0700 hrs.) with free accessto food and water.

Drug Administration

Test Compound is dissolved in either 100% DMSO or 5% lactic acid, v/v(Sigma Chemical Co., St. Louis, Mo.). Chlordiazepoxide (Sigma ChemicalCo., St. Louis, Mo.) is dissolved in double distilled water. The vehicleconsists of 50% DMSO (v/v) or 100% dimethylacetamide (DMA). All drugsolutions are made up 10 minutes prior to injection and the solutionsare discarded at the end of the test day. The volume of drug solutionadministered is 1 ml/kg.

Data Analysis

The social interaction data (time interacting, rearing and squarescrossed) are subjected to a randomized, one-way ANOVA and post hoc testsconducted using the Student-Newman-Keuls test. The data are subjected toa test of normality (Shapiro-Wilk test). The data are analyzed using theGBSTAT program, version 6.5 (Dynamics Microsystems, Inc., Silver Spring,Md., 1997).

In Vivo Models of the Micturition Reflex

The effects of compounds on the micturition reflex were assessed in the“distension-induced rhythmic contraction” (DIRC), as described inprevious publications (e.g. Maggi et al, 1987; Morikawa et al, 1992),and Continuous Slow Transvesicular Infusion (CSTI) models in rats.

DIRC Model

Female Sprague Dawley rats weighing approximately 300 g wereanesthetized with subcutaneous urethane (1.2 g/kg). The trachea wascannulated with PE240 tubing to provide a clear airway throughout theexperiment. A midline abdominal incision was made and the left and rightureters were isolated. The ureters were ligated distally (to preventescape of fluids from the bladder) and cannulated proximally with PE10tubing. The incision was closed using 4-0 silk sutures, leaving the PE10lines routed to the exterior for the elimination of urine. The bladderwas canulated via the transurethral route using PE50 tubing inserted 2.5cm beyond the urethral opening. This cannula was secured to the tailusing tape and connected to a pressure transducer. To prevent leakagefrom the bladder, the cannula was tied tightly to the exterior urethralopening using 4-0 silk. To initiate the micturition reflex, the bladderwas first emptied by applying pressure to the lower abdomen, and thenfilled with normal saline in 100 increments (maximum=2 ml) untilspontaneous bladder contractions occurred (typically 20-40 mmHg at arate of one contraction every 2 to 3 minutes. Once a regular rhythm wasestablished, vehicle (saline) or Test Compounds were administered i.v.or i.p. to explore their effects on bladder activity. The 5-HT_(1A)antagonist WAY-100635 was given as a positive control. Data wereexpressed as contraction interval (in seconds) before drug application(basal), or after the application of vehicle or test article.

Continuous Slow Transvesicular Infusion (CSTI) Rat Model

Male Sprague Dawley rats weighing approximately 300 g were used for thestudy. Rats were anaesthetized with pentobarbitone sodium (50 mg/kg,i.p). Through a median abdominal incision, bladder was exposed and apolyethylene cannula (PE 50) was introduced into the bladder through asmall cut on the dome of the bladder and the cannula was secured with apurse string suture. The other end of the cannula was exteriorizedsubcutaneously at the dorsal neck area. Similarly, another cannula (PE50) was introduced into the stomach through a paramedian abdominalincision with the free end exteriorized subcutaneously to the neckregion. The surgical wounds were closed with silk 4-0 suture and theanimal was allowed to recover with appropriate post surgical care. Onthe following day, the animal was placed in a rat restrainer. The openend of the bladder-cannula was connected to a pressure transducer aswell as infusion pump through a three-way stopcock. The bladder voidingcycles were initiated by continuous infusion of normal saline at therate of 100 μl/min. The repetitive voiding contractions were recorded ona Power Lab on-line data acquisition software. After recording the basalvoiding pattern for an hour, the test drug or vehicle was administereddirectly into stomach through the intragastric catheter and the voidingcycles were monitored for 5 hours. Micturition pressure and frequencywere calculated before and after the treatment (at every 30 mininterval) for each animal. Bladder capacity was calculated from themicturition frequency, based on the constant infusion of 100 μl/min. Theeffect of the test drug was expressed as a percentage of basal, pre-drugbladder capacity. WAY 100635 was used as positive control forcomparison. TABLE 2 In Vivo Results Effect of MCH1 antagonist (ExampleNo.) in the following in vivo models: 3-day Body Weight (3D BW), mouseSweetened Condensed Milk (mSwCM), mouse Forced Swim Test (mFST), ratForced Swim Test (rFST), DIRC model, or CSTI model. Ex- ample No. 3D BWmSwCM mFST RFST DIRC CSTI 1 Not tested Not tested No Not tested Nottested F effect 3 Not tested Not tested Not Not tested Not tested Ftested 4 Not tested Not tested C Not tested Not tested F 6 Not testedNot tested C Not tested Not tested F 8 Not tested Not tested C Nottested Not tested F 24 Not tested Not tested Not Not tested Not tested Ftested 29 Not tested Not tested Not Not tested Not tested F tested 32Not tested Not tested Not Not tested Not tested F tested 35 Not testedNot tested C Not tested Not tested FA = Produced a significant reduction in weight gain relative tovehicle-treated controlsB = Produced a significant decrease in consumption of milk relative tovehicle-treated controlsC = Produced a significant decrease in immobility relative tovehicle-treated animals when administered orally.D = Produced a significant decrease in immobility or a significantincrease in swimming activity relative to vehicle-treated animalsE = Produced a significant increase in contraction interval relative topre-drug intervalF = Produced an increase in bladder capacity in rats relative tobaseline capacity.

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1-38. (canceled)
 39. A method of treating a subject suffering fromdepression comprising administering to the subject a therapeuticallyeffective amount of a compound having the structure:

wherein each R₁ is independently hydrogen; —F; —Cl; —Br; —I; —CN; —NO₂;straight chained or branched C₁-C₇ alkyl, monofluoroalkyl orpolyfluoroalkyl; straight chained or branched C₂-C₇ alkenyl; C₃-C₇cycloalkyl or C₅-C₇ cycloalkenyl; aryl; heteroaryl; —N(R₅)₂;—(CH₂)_(m)OR₅; —COR₅; —CO₂R₅; —OCOR₅; —CON(R₅)₂; —N(R₅)COR₅;—N(R₅)CON(R₅)₂; —OCON(R₅)₂ or —N(R₅)CO₂R₅; wherein R₂ is hydrogen; —F;—Cl; —Br; —I; —CN; —(CH₂)_(m)OR₅; —(CH₂)_(m)SR₅; —NH₂; straight chainedor branched C₁-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl; aryl orheteroaryl, wherein the aryl or heteroaryl may be substituted with oneor more R₁ wherein R₃ is hydrogen; —F; —Cl; —Br; —I; —CN; —(CH₂)_(m)OR₅;—(CH₂)_(m)SR₅; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, polyfluoroalkyl; aryl or heteroaryl, wherein the arylor heteroaryl may be substituted with one or more R₁; or wherein R₂ andR₃ together can be —(CH₂)_(p)—; wherein R₄ is straight chained orbranched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl, C₃-C₆cycloalkyl, C₁-C₇ alkyl-C₃-C₆ cycloalkyl; —N(R₅)₂ or —(CH₂)_(m)OR₅;wherein each R₅ is independently hydrogen; aryl; heteroaryl or straightchained or branched C₁-C₇ alkyl, wherein the alkyl may be substitutedwith an aryl or heteroaryl; wherein each R₆ is independently hydrogen;straight chained or branched C₁-C₇ alkyl; wherein each R₇ isindependently hydrogen; phenyl or straight chained or branched C₁-C₇alkyl, wherein the alkyl may be substituted with a phenyl; wherein eachm is independently an integer from 0 to 5 inclusive; wherein n is aninteger from 1 to 5 inclusive; wherein p is an integer from 2 to 7inclusive; wherein q is an integer from 0 to 2 inclusive; and whereineach X is independently CR₁ or N, provided that if one X is N then theremaining X are CR₁; or a pharmaceutically acceptable salt thereof. 40.The method of claim 39, wherein the compound has the structure:


41. The method of claim 40, wherein the compound has the structure:

wherein R₂ and R₃ are each independently hydrogen; —F; —Cl; —Br; —I;—CN; —(CH₂)_(m)OR₅; —(CH₂)_(m)SR₅; straight chained or branched C₁-C₇alkyl, monofluoroalkyl, polyfluoroalkyl; aryl or heteroaryl, wherein thearyl or heteroaryl may be substituted with one or more R₁; or wherein R₂and R₃ together can be —(CH₂)_(p)—; wherein R₄ is straight chained orbranched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl, C₃-C₆cycloalkyl, —N(R₅)₂ or —(CH₂)_(m)OR₅; and X is CH or N.
 42. The methodof claim 41, wherein X is CH.
 43. The method of claim 41, wherein X isN.
 44. A method of treating a subject suffering from anxiety comprisingadministering to the subject a therapeutically effective amount of acompound having the structure:

wherein each R₁ is independently hydrogen; —F; —Cl; —Br; —I; —CN; —NO₂;straight chained or branched C₁-C₇ alkyl, monofluoroalkyl orpolyfluoroalkyl; straight chained or branched C₂-C₇ alkenyl; C₃-C₇cycloalkyl or C₅-C₇ cycloalkenyl; aryl; heteroaryl; —N(R₅)₂;—(CH₂)_(m)OR₅; —COR₅; —CO₂R₅; —OCOR₅; —CON(R₅)₂; —N(R₅)COR₅;—N(R₅)CON(R₅)₂; —OCON(R₅)₂ or —N(R₅)CO₂R₅; wherein R₂ is hydrogen; —F;—Cl; —Br; —I; —CN; —(CH₂)_(m)OR₅; —(CH₂)_(m)SR₅; —NH₂; straight chainedor branched C₁-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl; aryl orheteroaryl, wherein the aryl or heteroaryl may be substituted with oneor more R₁ wherein R₃ is hydrogen; —F; —Cl; —Br; —I; —CN; —(CH₂)_(m)OR₅;—(CH₂)_(m)SR₅; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, polyfluoroalkyl; aryl or heteroaryl, wherein the arylor heteroaryl may be substituted with one or more R₁; or wherein R₂ andR₃ together can be —(CH₂)_(p)—; wherein R₄ is straight chained orbranched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl, C₃-C₆cycloalkyl, C₁-C₇ alkyl-C₃-C₆ cycloalkyl; —N(R₅)₂ or —(CH₂)_(m)OR₅;wherein each R₅ is independently hydrogen; aryl; heteroaryl or straightchained or branched C₁-C₇ alkyl, wherein the alkyl may be substitutedwith an aryl or heteroaryl; wherein each R₆ is independently hydrogen;straight chained or branched C₁-C₇ alkyl; wherein each R₇ isindependently hydrogen; phenyl or straight chained or branched C₁-C₇alkyl, wherein the alkyl may be substituted with a phenyl; wherein eachm is independently an integer from 0 to 5 inclusive; wherein n is aninteger from 1 to 5 inclusive; wherein p is an integer from 2 to 7inclusive; wherein q is an integer from 0 to 2 inclusive; and whereineach X is independently CR₁ or N, provided that if one X is N then theremaining X are CR₁; or a pharmaceutically acceptable salt thereof. 45.The method of claim 44, wherein the compound has the structure:


46. The method of claim 45, wherein the compound has the structure:

wherein R₂ and R₃ are each independently hydrogen; —F; —Cl; —Br; —I;—CN; —(CH₂)_(m)OR₅; —(CH₂)_(m)SR₅; straight chained or branched C₁-C₇alkyl, monofluoroalkyl, polyfluoroalkyl; aryl or heteroaryl, wherein thearyl or heteroaryl may be substituted with one or more R₁; or wherein R₂and R₃ together can be —(CH₂)_(p)—; wherein R₄ is straight chained orbranched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl, C₃-C₆cycloalkyl, —N(R₅)₂ or —(CH₂)_(m)OR₅; and X is CH or N.
 47. The methodof claim 46, wherein X is CH.
 48. The method of claim 46, wherein X isN.
 49. A method of treating a subject suffering from obesity comprisingadministering to the subject a therapeutically effective amount of acompound having the structure:

wherein each R₁ is independently hydrogen; —F; —Cl; —Br; —I; —CN; —NO₂;straight chained or branched C₁-C₇ alkyl, monofluoroalkyl orpolyfluoroalkyl; straight chained or branched C₂-C₇ alkenyl; C₃-C₇cycloalkyl or C₅-C₇ cycloalkenyl; aryl; heteroaryl; —N(R₅)₂;—(CH₂)_(m)OR₅; —COR₅; —CO₂R₅; —OCOR₅; —CON(R₅)₂; —N(R₅)COR₅;—N(R₅)CON(R₅)₂; —OCON(R₅)₂ or —N(R₅)CO₂R₅; wherein R₂ is hydrogen; —F;—Cl; —Br; —I; —CN; —(CH₂)_(m)OR₅; —(CH₂)_(m)SR₅; —NH₂; straight chainedor branched C₁-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl; aryl orheteroaryl, wherein the aryl or heteroaryl may be substituted with oneor more R₁ wherein R₃ is hydrogen; —F; —Cl; —Br; —I; —CN; —(CH₂)_(m)OR₅;—(CH₂)_(m)SR₅; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, polyfluoroalkyl; aryl or heteroaryl, wherein the arylor heteroaryl may be substituted with one or more R₁; or wherein R₂ andR₃ together can be —(CH₂)_(p)—; wherein R₄ is straight chained orbranched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl, C₃-C₆cycloalkyl, C₁-C₇ alkyl-C₃-C₆ cycloalkyl; —N(R₅)₂ or —(CH₂)_(m)OR₅;wherein each R₅ is independently hydrogen; aryl; heteroaryl or straightchained or branched C₁-C₇ alkyl, wherein the alkyl may be substitutedwith an aryl or heteroaryl; wherein each R₆ is independently hydrogen;straight chained or branched C₁-C₇ alkyl; wherein each R₇ isindependently hydrogen; phenyl or straight chained or branched C₁-C₇alkyl, wherein the alkyl may be substituted with a phenyl; wherein eachm is independently an integer from 0 to 5 inclusive; wherein n is aninteger from 1 to 5 inclusive; wherein p is an integer from 2 to 7inclusive; wherein q is an integer from 0 to 2 inclusive; and whereineach X is independently CR₁ or N, provided that if one X is N then theremaining X are CR₁; or a pharmaceutically acceptable salt thereof. 50.The method of claim 49, where the compound has the structure:


51. The method of claim 50, wherein the compound has the structure:

wherein R₂ and R₃ are each independently hydrogen; —F; —Cl; —Br; —I;—CN; —(CH₂)_(m)OR₅; —(CH₂)_(m)SR₅; straight chained or branched C₁-C₇alkyl, monofluoroalkyl, polyfluoroalkyl; aryl or heteroaryl, wherein thearyl or heteroaryl may be substituted with one or more R₁; or wherein R₂and R₃ together can be —(CH₂)_(p)—; wherein R₄ is straight chained orbranched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl, C₃-C₆cycloalkyl, —N(R₅)₂ or —(CH₂)_(m)OR₅; and X is CH or N.
 52. The methodof claim 51, wherein X is CH.
 53. The method of claim 51, wherein X isN.